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At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

The proteolytic activity of the reaction mixtures was determined using Bz-DL-Arg-pNA as the chromogenic substrate . To solutions of active papain final concentration: 0.05 mM were added concentrated solutions of the different derivatives to final concentrations of 0.2 mM. After incubation for 30 min at 37uC, the substrate solution was added and after a further incubation for 20 min the reaction was stopped by the addition of 5% trichloric acid TCA acidified with 2.25% HCl and the absorbance of the reaction mixture was determined at a wavelength of 410 nm by Microplate Manager 4.0 Bio-Rad laboratories .

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

DMSO was taken as negative control and Ceftriaxone and clotrimazole were taken as positive control. After incubation at 37uC overnight, the MICs were taken as the lowest inhibitor concentration at which the bacterial growth was inhibited. The average of three values was calculated and that was the MIC for the test material and bacterial strain.

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

After having determined the MICs, bacterial strains from the wells of the microtitre plate with no visible bacterial growth were removed for serial sub cultivation of 2 ml into another new microtitre plate containing 100 ml of broth per well and further incubated for 24 h. The lowest concentration with no visible growth was defined as MBC , indicating 99.5% killing of the original inoculum. The absorbance of each well was measured at a wavelength of 620 nm by Microplate Manager 4.0 Bio-Rad laboratories and compared with a blank. Solvent DMSO was used as a negative control.

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

Subsequently, compounds were synthesized to validate their efficacy in wet lab experiments. When characterized kinetically, these compounds show their K i and IC. values in the range of 13.75 to 99.30 µM and 13.40 to 96.50 µM, respectively. The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven.

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

The number of docking runs was set to 10. Each docking was repeated five times, having in the end a total of 50 docking runs, to check the precision of results. The finally obtained docked complexes were subsequently visualized using PyMol .

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

In brief, the bacterial strains S. aureus, P. vulgaris, Group D Streptococci, Bacillus sp., E. coli, P. aeruginosa and S. morganii were grown and diluted to 2610 5 colony-forming units CFU /ml in sodium phosphate buffer SPB containing 0.03% Luria-Bertani LB broth. The synthesized derivatives were dissolved in DMSO and their serial dilution was performed in 50 mL of LB medium in 96-well microtitre plate to achieve the required concentrations 0.1-10 mg/ml with bacterial inoculums 5610 4 CFU per well . DMSO was taken as negative control and Ceftriaxone and clotrimazole were taken as positive control.

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

The active site residues that were found to be key player in the interaction of compounds within the active site mostly through hydrophobic interactions were Cys25, Tyr61, His159 and Trp177, while Trp177, Gln19 were found to me making hydrogen bonds only with compound 3a. Besides this many other residues were also found to be actively involved Table 1 . Furthermore, the binding energies for the compound 3a, 3b, 3c and 3d with papain were found to be 26.12, 25.76, 26.84 and 25.62 Kcal/mol respectively, which were in great agreement with our wet lab experiments; shall be discussed later Table 1 .

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

Prediction of antibacterial compounds as drugs Table 2 . Interestingly, the observed in silico binding energies for the compounds 3a-d against papain were found to be in great agreement standard error 62 Kcal/mol with the value of free energy of binding DG observed during thermodynamics studies Table 1 and 2 . Similarly, enthalpy change DH of the binding was negative whereas entropy DS change of the binding was positive which indicated the exothermic and entropically driven nature of binding.

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives. The MIC 50 of these derivatives, showing inhibition in the preliminary tests, were further determined by the microtitre plate technique using micro dilution method . In brief, the bacterial strains S. aureus, P. vulgaris, Group D Streptococci, Bacillus sp., E. coli, P. aeruginosa and S. morganii were grown and diluted to 2610 5 colony-forming units CFU /ml in sodium phosphate buffer SPB containing 0.03% Luria-Bertani LB broth.

At what temperatures was the assay completed?

Changes in enthalpy DH were determined from the Van't Hoff plots by using the equation, Where DH is enthalpy change, R is gas constant, DS is entropy change and T is the absolute temperature. The entropy change was obtained from the equation, The assay was done at different temperatures 32uC, 37uC, 42uC calculating various K i of 1-pyridylimidazo 1,5-a pyridine derivatives with papain as model enzyme. The disk diffusion method was used for the preliminary antibacterial evaluation of 1-pyridylimidazo 1,5-a pyridine derivatives.

Similarly, enthalpy change DH of the binding was negative whereas entropy DS change of the binding was positive which indicated the exothermic and entropically driven nature of binding. This pattern of temperature dependence is characteristic of hydrophobic interaction . As discussed earlier that all the compounds 3a-d were found to interact with the active site residues of papain through hydrophobic interactions at most instances during in silico studies, the same was observed by the analysis of Van't Hoff plots for all the proposed inhibitors at three different temperatures 32uC, 37uC and 42uC in wet lab experiments Figure 3 .

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

All the compounds studied except 3d, showed good agreement with the criteria laid down for the prediction of a compound to be a potential drug Table 5 . All the compounds do not show any threat against toxicity risk assessment except compound 3d which showed threat as tumorogenic effect due to the presence of isobutyl group. Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

The finally obtained docked complexes were subsequently visualized using PyMol . The work was further authenticated in the wet lab after its detailed analysis on in silico platform. The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

N N py? Form = admetox N The above study gave us an idea about the existence of possible mutagenic and tumorigenic properties in synthesized compounds. The result obtained helped us to screen out the synthesized compounds for their further usage as potent leads.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

They have been shown to possess a broad range of useful pharmacological activities including antigastric, antisecretory, local anesthetic, antiviral, antianxiety, antibacterial, antifungal, antihelminthic, antiprotozoal, anticonvulsant, gastrointestinal, antiulcer Zolmidine , anxiolytic Alpidem , hypnotic Zolpidem and immunomodulatory . The nature and the position of the substituents on the pyridinic moiety influence these pharmacological activities. These imidazopyridine heterocyclic structures form part of the skeleton of natural alkaloids, neuromuscular blocking agents , reversible inhibitors of the H + , K + -ATPase enzymes with a potent antisecretory activity, and are known to be sedative hypnotics of the nervous system .

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

The partition coefficient logP is a well-established measure of the compound's lipophilicity. The distribution of calculated logP cLogP values of a majority of drugs in the market is in the range of zero to five. All the compounds studied except 3d, showed good agreement with the criteria laid down for the prediction of a compound to be a potential drug Table 5 .

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

Subsequently, compounds were synthesized to validate their efficacy in wet lab experiments. When characterized kinetically, these compounds show their K i and IC. values in the range of 13.75 to 99.30 µM and 13.40 to 96.50 µM, respectively. The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

Prediction of antibacterial compounds as drugs Table 2 . Interestingly, the observed in silico binding energies for the compounds 3a-d against papain were found to be in great agreement standard error 62 Kcal/mol with the value of free energy of binding DG observed during thermodynamics studies Table 1 and 2 . Similarly, enthalpy change DH of the binding was negative whereas entropy DS change of the binding was positive which indicated the exothermic and entropically driven nature of binding.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 . In silico absorption, distribution, metabolism and excretion ADME properties of these derivatives were also predicted using following online bioinformatics tools. N N py?

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven. These inhibitors also inhibit the growth of clinically important different types of Gram positive and Gram negative bacteria having MIC. values in the range of 0.6–1.4 µg/ml. Based on Lipinski’s rule of Five, we also propose these compounds as potent antibacterial prodrugs.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

Since, pyridylimidazo 1,5-a pyridine derivatives is absolutely new scaffold towards antibacterial agents and hence, not any standard compound s of same scaffold is available for reference. So, Clotrimazole 1- 2-chlorophenyl diphenyl methyl -1H-imidazole , an imidazole derivatives and Ceftriaxone third-generation cephalosporin antibiotic with broad spectrum activity against Gram-positive and Gram-negative bacteria have been used as positive control whereas DMSO has been used as negative control. All the above mentioned bacterial species have been shown to secrete certain cysteine proteases which play very important role in the pathogenecity of different diseases caused by these microorganisms.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

All the compounds strictly followed the pattern of antiprotease activity towards bacterial growth except P. vulgaris and E. coli at one instance each Table 4 . Since compound 3c & 3d do not have much difference in their IC50 values 3c-94.5 mM and 3d-96.5 mM against cysteine protease, papain and hence in antibacterial activity in all instances except one. It might be random due to so close in IC50 values.

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

The key role of cysteine proteases in microbial infections, coupled with the relative lack of redundancy compared to mammalian systems has made microbial proteases attractive targets for the development of novel chemotherapeutic approaches . Imidazopyridine ring systems represent an important class of compounds not only for their theoretical interest but also from a pharmacological point of view. They have been shown to possess a broad range of useful pharmacological activities including antigastric, antisecretory, local anesthetic, antiviral, antianxiety, antibacterial, antifungal, antihelminthic, antiprotozoal, anticonvulsant, gastrointestinal, antiulcer Zolmidine , anxiolytic Alpidem , hypnotic Zolpidem and immunomodulatory .

What criteria sets the guideline for drug-like properties?

The designed derivatives were filtered by Lipinski's ''Rule of five'' that sets the criteria for drug-like properties. Drug likeness is a property that is most often used to characterize novel lead compounds . According to this rule, poor absorption is expected if MW .500, log P.5, hydrogen bond donors .5, and hydrogen bond acceptors .10 .

These imidazopyridine heterocyclic structures form part of the skeleton of natural alkaloids, neuromuscular blocking agents , reversible inhibitors of the H + , K + -ATPase enzymes with a potent antisecretory activity, and are known to be sedative hypnotics of the nervous system . In this study, we have proposed kinetically and thermodynamically characterized 1-substituted pyridylimidazo 1,5-a pyridine derivatives as a potent and novel cysteine protease inhibitors which also acts as antibacterial agents. The crystal structure of papain was extracted from Protein Data Bank PDB code: 1PE6 .

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Targeting papain family cysteine proteases is one of the novel strategies in the development of chemotherapy for a number of diseases. Novel cysteine protease inhibitors derived from 1-pyridylimidazo 1,5-a pyridine representing pharmacologically important class of compounds are being reported here for the first time. The derivatives were initially designed and screened in silico by molecular docking studies against papain to explore the possible mode of action.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

In sum up, the above results of molecular docking studies and thermodynamic analysis of compounds 3a-d with papain showed that these compounds have the potential to be novel and unique cysteine protease inhibitors. In the current study, the cysteine protease inhibitory activity of synthesized derivatives of 1-substituted pyridylimidazo 1,5-a pyridine 3a-d was also performed against papain and the inhibition constants K i for the above said enzyme were observed to be 13.70, 23.20, 90.00 and 99.30 mM for compounds 3a, 3b, 3c and 3d respectively Table 3 . Furthermore, the calculated IC 50 values were also found to be 13.40, 21.17, 94.50 and 96.50 mM for compounds 3a, 3b, 3c and 3d respectively Table 3 .

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Text: Cysteine-protease inhibitors CPI have gained considerable attention over the last couple of decades and many classes of compounds are currently in human clinical trials for a number of diseases. Interest in papain family cysteine proteases as chemotherapeutic targets is derived from the recognition that they are critical to the life cycle or pathogenicity of many microorganisms. The cysteine proteases from Streptococcus sp.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven. These inhibitors also inhibit the growth of clinically important different types of Gram positive and Gram negative bacteria having MIC. values in the range of 0.6–1.4 µg/ml. Based on Lipinski’s rule of Five, we also propose these compounds as potent antibacterial prodrugs.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

As a part of our investigation in developing novel and efficient cysteine protease inhibitors, ten 1-substituted pyridylimidazo 1,5a pyridine derivatives 3a-j were primarily designed and screened on the basis of their docking energies against papain to elucidate their possible mode of action. It was found that these compounds were specific inhibitors of cysteine protease, papain and didn't show inhibition against other types of proteases like serine, aspartic or metalloproteases. They are specific for CA clan of cysteine protease and didn't show any significant inhibition against other clans of cysteine proteases.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Recently described cystatin superfamily of proteins comprises both eukaryotic and prokaryotic cysteine protease inhibitors . Human cystatins C, D and S, rat cystatins A and S, chicken cystatin and oryza cystatin have been reported to inhibit the replication of certain viruses and bacteria although it has not yet been directly demonstrated that these effects are due to the protease inhibitory capacity of the cystatins . The key role of cysteine proteases in microbial infections, coupled with the relative lack of redundancy compared to mammalian systems has made microbial proteases attractive targets for the development of novel chemotherapeutic approaches .

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Like serine proteases, cysteine proteases tend to have relatively shallow, solvent-exposed active sites that can accommodate short substrate/inhibitor segments of protein loops e.g. from endogenous inhibitors such as cystatins or strands. The inhibitor Table 3 . Name, Structure, IC50 & K i of 1-substituted pyridylimidazo 1,5-a pyridine derivatives against cysteine protease papain.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Name, Structure, IC50 & K i of 1-substituted pyridylimidazo 1,5-a pyridine derivatives against cysteine protease papain. Type of inhibition Ki mM IC 50 mM Non-Competitive 13.7 13.4 compound bound to protease with a combination of hydrogen bonds and hydrophobic interactions. As a part of our investigation in developing novel and efficient cysteine protease inhibitors, ten 1-substituted pyridylimidazo 1,5a pyridine derivatives 3a-j were primarily designed and screened on the basis of their docking energies against papain to elucidate their possible mode of action.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

have potent metallo-, cysteine and serine proteases with broad ranges of activities . The critical role of bacterial proteases in virulence was successfully demonstrated by eliminating the proteaseencoding gene in P. gingivalis . Recently described cystatin superfamily of proteins comprises both eukaryotic and prokaryotic cysteine protease inhibitors .

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

All the above mentioned bacterial species have been shown to secrete certain cysteine proteases which play very important role in the pathogenecity of different diseases caused by these microorganisms. The minimum inhibitory concentration MICs of compounds 3a-d Table 4 against all tested bacteria except E. coli and P. vulgaris, were observed to be in great agreement with their respective inhibition constant K i /IC 50 values against papain Table 3 which clearly indicates that these compounds have the potential to inhibit the papain like cysteine proteases of these pathogens. The partition coefficient logP is a well-established measure of the compound's lipophilicity.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Since, the binding energy is a direct measure of strength of interaction and our compounds 3a-d showed stronger binding within the active site of papain in comparison to the inhibitor E-64c DG: 24.04 Kcal/mol , therefore, the results suggest that these 1-substituted pyridylimidazo 1,5-a pyridine derivatives 3ad could be potent inhibitors of papain like cysteine proteases. The in silico interaction of compounds 3a-d with papain, which were observed as discussed above, was validated with wet lab Table 5 . Prediction of antibacterial compounds as drugs Table 2 .

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Hence, thermodynamics as well as in silico study reveals that hydrophobic interactions favor binding of these proposed inhibitors with papain like cysteine proteases. Further wet lab results proposed the non competitive interaction of compounds 3a, 3c & 3d with papain except for compound 3b which showed competitive interaction. In sum up, the above results of molecular docking studies and thermodynamic analysis of compounds 3a-d with papain showed that these compounds have the potential to be novel and unique cysteine protease inhibitors.

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

These imidazopyridine heterocyclic structures form part of the skeleton of natural alkaloids, neuromuscular blocking agents , reversible inhibitors of the H + , K + -ATPase enzymes with a potent antisecretory activity, and are known to be sedative hypnotics of the nervous system . In this study, we have proposed kinetically and thermodynamically characterized 1-substituted pyridylimidazo 1,5-a pyridine derivatives as a potent and novel cysteine protease inhibitors which also acts as antibacterial agents. The crystal structure of papain was extracted from Protein Data Bank PDB code: 1PE6 .

What could be novel candidates as potent inhibitors of papain like cysteine proteases in resistant microorganisms?

Among all the tested compounds, compound 3a was the most potent whose MIC was the lowest among all the tested compounds and showed maximum drug score and positive values for drug likeness. In summary, the results of the present study have established that 1-substituted pyridylimidazo 1,5-a pyridine derivatives could be candidate for novel and potent inhibitors of papain like cysteine proteases, which play deleterious role in the progression of different diseases caused by diverse microorganisms. Therefore, this group of compounds could be the subject of future research to confront the challenges with resistant microorganisms that is a major threat globally.

Although, E. coli does contain six major cysteine proteases but none belong to the CA clan of papain. It is argued that these compounds also inhibited the cysteine proteases of other clan than papain but with low efficacy. Since, pyridylimidazo 1,5-a pyridine derivatives is absolutely new scaffold towards antibacterial agents and hence, not any standard compound s of same scaffold is available for reference.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs. Phase II clinical trials have been initiated for the treatment of respiratory syncytial virus RSV infection, making use of intranasal application of naked chemically modified siRNA molecules that target viral gene products see Section 3.1.1. for details . Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Ongoing research into the transfection of primary cells and whole organisms with siRNA using non-viral transfection agents has produced some promising results. Lipid-based delivery vectors are successfully used to deliver siRNA in vitro and in vivo . Cationic lipids are composed of positively charged head, a linker and hydrophobic.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

It is generally acknowledged that the critical factor for efficient siRNA delivery depends on the properties of RNAi drug particles in terms of size, charge, shape, velocity and density. For efficient pulmonary siRNA delivery, the particles must be deposited in the lower respiratory tract. Deposition in the airway is affected by the particle size and patient's pulmonary function.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

It is important to maintain a clear view of the trachea during the procedure. Intranasal delivery is another common method of pulmonary drug application in animal studies. In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 .

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Many commercial siRNA transfection agents are lipid-based delivery system, some of which are also employed for pulmonary delivery-DharmFECT , Oligofectamine , Lipofectamine and TransIT-TKO . Similarly, cationic polymers have also been assessed for siRNA delivery to lung cells. Cationic polymer polyethylenimine PEI is widely used for siRNA delivery .

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Pulmonary delivery applications are very attractive, since they tend to be non-invasive, are locally restricted, and can be administered by the patient. A realistic therapeutic intervention, such as aerosolization, can enhance drug delivery to the site of action and decrease systemic exposure of the patient to the therapy, thereby reducing off-target effects. The advancement of pulmonary siRNA delivery to the clinic illustrates that RNAi-based therapy holds a central place in the future treatment of lung diseases.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 . An experimental setup of intranasal delivery by spray or droplet is simple and painless for the animal. Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

An ideal delivery agent should protect siRNAs from enzymatic degradation, facilitate cellular uptake, and promote endosomal escape inside the cells with negligible toxicity. Multiple approaches for the delivery of siRNAs have been reported, ranging from the relatively simple direct administration of saline-formulated siRNAs to lipid-based and polymer-based nanoparticle approaches and siRNA conjugation and complexation approaches . The negative charge and chemical degradability of siRNAs under physiologically relevant conditions make its delivery a major challenge.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Careful choice of efficient delivery in response to the condition of lung diseases is necessary. The use of aerosols to deliver medication to the lungs has a long history. Administration by inhalation is a popular and non-invasive method of delivering agents into the lungs. There are several inhalation devices available for the delivery of drugs into the lungs.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

The intranasal method is suitable for some lung diseases, such as upper respiratory infection by RSV, and it also has potential for systemic delivery rather than pulmonary delivery of siRNAs. Therefore, it is important to consider the route of administration in animal studies when assessing the delivery and therapeutic efficacy of a formulation for pulmonary delivery. Careful choice of efficient delivery in response to the condition of lung diseases is necessary.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract. In fact, it has been reported that intranasal application of unformulated siRNAs resulted in lower delivery efficiency and homogeneous pulmonary distribution than that achieved with intratracheal application . The intranasal method is suitable for some lung diseases, such as upper respiratory infection by RSV, and it also has potential for systemic delivery rather than pulmonary delivery of siRNAs.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

To direct target-gene silencing, the siRNAs need to escape from the endosome into the cytoplasm, where they associate with the Ago2/RNA-induced silencing complex RISC to direct the cleavage of mRNAs bearing complementary binding sites. As an alternative to viral vectors, non-viral vectors, including lipid and polymer-based vectors, have been generally used for the delivery of siRNAs to the lungs due to their reduced toxicity . Ongoing research into the transfection of primary cells and whole organisms with siRNA using non-viral transfection agents has produced some promising results.

What method is useful in administering small molecules for systemic delivery to the body?

let-7 is a tumor-suppressor miRNA in non-small-cell lung cancer that inversely correlates with the expression of the RAS oncoprotein, a key cancer gene . Intranasal administration of let-7 mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that miRNA replacement therapy is indeed promising . Another miRNA that shows the value of miRNA replacement is provided by miR-34a .

The use of spray-drying as a technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local delivery of biologically active siRNA directly to the lung tissue, has been demonstrated . In the future, the technique is desirable to estimate the in vivo study on siRNA therapy for inhalation. In the long term, we anticipate that there will be more sophisticated devices for clinical use and that those currently being developed will be more suitable.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

Mucus and mucociliary clearance of mucus-trapped particles is a pulmonary defense mechanism as a physiological barrier. In the alveolar, clara cells and type II alveolar cells secrete on the surface of the alveolar epithelium, forming a thin layer of pulmonary surfactants. The surfactants act as the main barrier for siRNA delivery because they reduce the transfection efficiency.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

The anatomical feature of the respiratory tract is its high degree of branching. The mucus lines the respiratory epithelium from the nasal cavity to the terminal bronchioles. The deposited particles on the ciliated epithelial cells are rapidly cleared by the mucociliary clearance actions. Mucus and mucociliary clearance of mucus-trapped particles is a pulmonary defense mechanism as a physiological barrier.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

Deposition in the airway is affected by the particle size and patient's pulmonary function. A particle size between 1-5 μm is found to be the most appropriate for deposition at the lower respiratory tract . In addition, the presence of mucus and surfactant proteins, the mucociliary clearance actions, and phagocytosis by macrophages present major barriers to targeted pulmonary delivery.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

Airway consists of respiratory bronchioles, alveolar ducts, and alveolar sacs. All of these structures bear alveoli, the tiny air sacs in which the gas exchange takes place. It is generally acknowledged that the critical factor for efficient siRNA delivery depends on the properties of RNAi drug particles in terms of size, charge, shape, velocity and density.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

The surfactants act as the main barrier for siRNA delivery because they reduce the transfection efficiency. In addition, the macrophages located in the alveoli rapidly engulf the foreign particles by phagocytosis. The particles taken up into the macrophages are subsequently degraded inside the cells. These factors present major barriers to targeted pulmonary delivery.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

In the long term, we anticipate that there will be more sophisticated devices for clinical use and that those currently being developed will be more suitable. There are two main barriers to efficient pulmonary siRNA delivery to the cells of the lung. The first is the complex, branched anatomy of the lungs and biomechanical barriers, such as the mucus layer covering the airway cells Figure 2 .

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

In addition, the presence of mucus and surfactant proteins, the mucociliary clearance actions, and phagocytosis by macrophages present major barriers to targeted pulmonary delivery. Therefore, delivery systems usually require delivery vectors, and these vectors need to be designed in order to maximize the siRNA deposition to the diseased area of the respiratory tract. Besides, the extracellular barriers to siRNA delivery also depend on physiological features of the respiratory tract, which may change with the disease stage and characteristics of the patient.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

The airway wall thickness, the high viscosity, and the composition of the mucus layer might be altered in patients who have inflammatory lung diseases. Figure 2 . Extracellular barriers to pulmonary siRNA delivery. The anatomical feature of the respiratory tract is its high degree of branching.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

For efficient endocytosis to occur, particles should be under 150 nm in size. Particles within this size range could also avoid macrophage uptake and delayed lung clearance . The physicochemical properties of siRNAs also play a significant role in crossing the biological membrane.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

It is generally acknowledged that the critical factor for efficient siRNA delivery depends on the properties of RNAi drug particles in terms of size, charge, shape, velocity and density. For efficient pulmonary siRNA delivery, the particles must be deposited in the lower respiratory tract. Deposition in the airway is affected by the particle size and patient's pulmonary function.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

These factors present major barriers to targeted pulmonary delivery. The second is the airway cell membrance and its intracellular barriers Figure 3 . For efficient gene silencing in the lungs, siRNAs must be delivered to their site of action, be stable, enter the target cells, and be present in the cytoplasm at sufficient concentration.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

During infection, inflammation, and allergic reaction, there is an increase in mucus secretion along with the impaired mucociliary clearance . Moreover, asthma and COPD are both chronic inflammatory conditions of the lung associated with structural "remodeling" that is inappropriate to the maintenance of normal lung function . The airway wall thickness, the high viscosity, and the composition of the mucus layer might be altered in patients who have inflammatory lung diseases.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

This explanation has not been confirmed, but the physiological damage of respiratory epithelial cells caused by viral infection may have possibly influenced the mystery. The active change in airway epithelial cell membrance caused by infectious disease might affect cellular internalization. Naked siRNA delivery has some advantages, such as simple formation and the absence of toxicity or inflammatory responses that are usually associated with delivery vectors.

Why is the nasal mucosa useful in the delivery of small molecules into the body?

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

The physicochemical properties of siRNAs also play a significant role in crossing the biological membrane. Despite their small size, the negative charge and chemical degradability of siRNA molecules prevent them from readily crossing biological membranes. Therefore, efficient siRNA delivery approaches need to overcome this limitation by facilitating cellular uptake.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Careful choice of efficient delivery in response to the condition of lung diseases is necessary. The use of aerosols to deliver medication to the lungs has a long history. Administration by inhalation is a popular and non-invasive method of delivering agents into the lungs. There are several inhalation devices available for the delivery of drugs into the lungs.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

It is important to maintain a clear view of the trachea during the procedure. Intranasal delivery is another common method of pulmonary drug application in animal studies. In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 .

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 . An experimental setup of intranasal delivery by spray or droplet is simple and painless for the animal. Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Many commercial siRNA transfection agents are lipid-based delivery system, some of which are also employed for pulmonary delivery-DharmFECT , Oligofectamine , Lipofectamine and TransIT-TKO . Similarly, cationic polymers have also been assessed for siRNA delivery to lung cells. Cationic polymer polyethylenimine PEI is widely used for siRNA delivery .

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Pulmonary delivery applications are very attractive, since they tend to be non-invasive, are locally restricted, and can be administered by the patient. A realistic therapeutic intervention, such as aerosolization, can enhance drug delivery to the site of action and decrease systemic exposure of the patient to the therapy, thereby reducing off-target effects. The advancement of pulmonary siRNA delivery to the clinic illustrates that RNAi-based therapy holds a central place in the future treatment of lung diseases.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

The intranasal method is suitable for some lung diseases, such as upper respiratory infection by RSV, and it also has potential for systemic delivery rather than pulmonary delivery of siRNAs. Therefore, it is important to consider the route of administration in animal studies when assessing the delivery and therapeutic efficacy of a formulation for pulmonary delivery. Careful choice of efficient delivery in response to the condition of lung diseases is necessary.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

It is generally acknowledged that the critical factor for efficient siRNA delivery depends on the properties of RNAi drug particles in terms of size, charge, shape, velocity and density. For efficient pulmonary siRNA delivery, the particles must be deposited in the lower respiratory tract. Deposition in the airway is affected by the particle size and patient's pulmonary function.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract. In fact, it has been reported that intranasal application of unformulated siRNAs resulted in lower delivery efficiency and homogeneous pulmonary distribution than that achieved with intratracheal application . The intranasal method is suitable for some lung diseases, such as upper respiratory infection by RSV, and it also has potential for systemic delivery rather than pulmonary delivery of siRNAs.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Therefore, the method is being used in animal models to test and evaluate its reliability for possible clinical applications. Intratracheal route: under anesthesia, the trachea is exposed surgically, and a tube or needle is inserted through an incision made between the tracheal rings. Complications, such as vascular injury and air leakage, are possible due to the tracheotomy.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Endotracheal applications are currently being used by many practitioners in the pulmonary field ; this is useful for studying pulmonary drug delivery in mice. However, the approach is more complex in humans because an artificial path for the delivery of drugs into the lungs is used. Therefore, the method is being used in animal models to test and evaluate its reliability for possible clinical applications.

What are the most common methods of inhaled delivery of medications?

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

Although CFCs in drugs are safe for patients to inhale, they are harmful to the environment. Therefore, further development of inhalable siRNAs may not be the best way forward. DPIs are devices that deliver medication to the lungs in the form of dry powder.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

The use of spray-drying as a technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local delivery of biologically active siRNA directly to the lung tissue, has been demonstrated . In the future, the technique is desirable to estimate the in vivo study on siRNA therapy for inhalation. In the long term, we anticipate that there will be more sophisticated devices for clinical use and that those currently being developed will be more suitable.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

There are several inhalation devices available for the delivery of drugs into the lungs. Metered dose inhalers MDIs and dry powder inhalers DPIs are the most common modes of inhaled delivery. MDIs are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease COPD , and a spacer is an external device that is attached to an MDI to allow for better drug delivery by enhanced actuation and inhalation coordination.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

Delivery to the lungs will be most important to moving siRNA technology into the clinic. A number of siRNA-based therapies are being evaluated in clinical trials for the treatment of different conditions, including lung diseases such as asthma and RSV infection. Table 1 is a summary of clinical trials of siRNA-based therapeutics .

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

Careful choice of efficient delivery in response to the condition of lung diseases is necessary. The use of aerosols to deliver medication to the lungs has a long history. Administration by inhalation is a popular and non-invasive method of delivering agents into the lungs. There are several inhalation devices available for the delivery of drugs into the lungs.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

Although CFCs in drugs are safe for patients to inhale, they are harmful to the environment. Therefore, further development of inhalable siRNAs may not be the best way forward. DPIs are devices that deliver medication to the lungs in the form of dry powder.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

It is important to maintain a clear view of the trachea during the procedure. Intranasal delivery is another common method of pulmonary drug application in animal studies. In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 .

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

Pulmonary delivery applications are very attractive, since they tend to be non-invasive, are locally restricted, and can be administered by the patient. A realistic therapeutic intervention, such as aerosolization, can enhance drug delivery to the site of action and decrease systemic exposure of the patient to the therapy, thereby reducing off-target effects. The advancement of pulmonary siRNA delivery to the clinic illustrates that RNAi-based therapy holds a central place in the future treatment of lung diseases.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process. A suitable carrier is also needed to protect nucleic acids from degradation due to shear force and increased temperature during the drying process. The use of spray-drying as a technique for engineering dry powder formulations of siRNA nanoparticles, which might enable the local delivery of biologically active siRNA directly to the lung tissue, has been demonstrated .

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

Many commercial siRNA transfection agents are lipid-based delivery system, some of which are also employed for pulmonary delivery-DharmFECT , Oligofectamine , Lipofectamine and TransIT-TKO . Similarly, cationic polymers have also been assessed for siRNA delivery to lung cells. Cationic polymer polyethylenimine PEI is widely used for siRNA delivery .

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

This evidence makes miRNAs a promising technology for current and future therapeutic development. We discuss the role of some miRNAs in various lung diseases as well as the possible future of these discoveries in clinical applications. Table 2 shows the summary of miRNAs in therapeutic development.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs. Phase II clinical trials have been initiated for the treatment of respiratory syncytial virus RSV infection, making use of intranasal application of naked chemically modified siRNA molecules that target viral gene products see Section 3.1.1. for details . Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 . An experimental setup of intranasal delivery by spray or droplet is simple and painless for the animal. Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs.

What medications have shown good promise to in vivo delivery via dry powder inhalers?

DPIs are devices that deliver medication to the lungs in the form of dry powder. The use of DPIs has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin and low-molecular-weight heparin ; thus, it could be a better device for delivering siRNAs to the lungs. The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation.

It is generally acknowledged that the critical factor for efficient siRNA delivery depends on the properties of RNAi drug particles in terms of size, charge, shape, velocity and density. For efficient pulmonary siRNA delivery, the particles must be deposited in the lower respiratory tract. Deposition in the airway is affected by the particle size and patient's pulmonary function.

How are siRNAs typically delivered for systemic effect?

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs. Phase II clinical trials have been initiated for the treatment of respiratory syncytial virus RSV infection, making use of intranasal application of naked chemically modified siRNA molecules that target viral gene products see Section 3.1.1. for details . Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery.

How are siRNAs typically delivered for systemic effect?

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

Intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. Because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. Therefore, siRNAs administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract.

How are siRNAs typically delivered for systemic effect?

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

Ongoing research into the transfection of primary cells and whole organisms with siRNA using non-viral transfection agents has produced some promising results. Lipid-based delivery vectors are successfully used to deliver siRNA in vitro and in vivo . Cationic lipids are composed of positively charged head, a linker and hydrophobic.

How are siRNAs typically delivered for systemic effect?

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

To direct target-gene silencing, the siRNAs need to escape from the endosome into the cytoplasm, where they associate with the Ago2/RNA-induced silencing complex RISC to direct the cleavage of mRNAs bearing complementary binding sites. As an alternative to viral vectors, non-viral vectors, including lipid and polymer-based vectors, have been generally used for the delivery of siRNAs to the lungs due to their reduced toxicity . Ongoing research into the transfection of primary cells and whole organisms with siRNA using non-viral transfection agents has produced some promising results.

How are siRNAs typically delivered for systemic effect?

The advantages of DPIs are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. Although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using siRNAs have relied on intratracheal or intranasal delivery. The reason could be the difficulty in formulating inhalable siRNAs and maintaining the stability during the delivery process.

In many studies, in vivo success has been demonstrated in delivering siRNAs to the lungs intranasally 22, 35, 36 . An experimental setup of intranasal delivery by spray or droplet is simple and painless for the animal. Although the success in delivering siRNAs intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy , this approach has potential for the clinical application of siRNAs.