A gyógyszerkutatás új irányzatai: hatékonyság és biztonságosság
Authors: Kotschy András 
Published: October 2021

Összefoglaló. A betegségek mögött meghúzódó biokémiai, sejtbiológiai
változások molekuláris szintű megértése a korszerű gyógyszerkutatás alapját
képezi. A kiválasztott biológiai célpont, leggyakrabban egy fehérje, működésének
gátlásától vagy fokozásától azt reméljük, hogy elősegíti a gyógyulást. A
hagyományos gyógyszerkutatási megközelítések molekuláris alapját a kiválasztott
fehérjével való közvetlen kölcsönhatás jelentette. Ugyanakkor a sejten belüli
molekuláris biológiai folyamatok részletesebb megértése több új megközelítést
nyitott a gyógyszerkutatás számára. A közlemény ezeket a gyógyszerkutatási
irányzatokat mutatja be, külön kitérve biztonságosságukra.

Summary. Human diseases originate from and are accompanied by
changes in the biochemistry of cells. The molecular level understanding of these
deviations from normal functioning is key to the curing of the diseases,
therefore a principal objective of drug discovery. The key-lock principle
postulated by Emil Fischer serves well the understanding of most enzymatic
processes and has been helping researchers both in academia and industry to
discover new drugs. The binding of a small molecule to the target protein and
inhibiting or activating its function is the basis for the efficient functioning
of a long list of current drugs. Sometimes the desired biological effect comes
from the selective action on a single protein, in other instances it is the
combined effect on the working of several proteins. The appropriate selectivity
profile is key to the safety and efficiency of the drug in both cases.

The completion of the Human Genome Project, in parallel with a significant
improvement in the performance of the analytical instrumentation, increased our
molecular and systemic level understanding of diseases immensely. Analysis of
the differences between healthy and diseased cells and tissues led to the
identification of new targets, a lot of which are not classical enzymes but
proteins exerting their effect through molecular interactions with other
proteins or nucleic acids. Although these proteins were considered undruggable
some decades ago, their disease modifying potential led to the discovery of new
approaches and modalities to target them. The inhibition of protein-protein
interactions, for example, requires the selective targeting of hydrophobic
surfaces, sometimes with very high affinity. Drug candidates acting through this
molecular mechanism are typically beyond the size of classical drugs that might
complicate their development.

Besides interacting directly with the protein of interest we might also impact
its working through manipulating its quantity within the cell. Interference with
the proteasomal degradation of cellular proteins, blocking its working, or
hijacking it to selectively increase the degradation of our protein of choice
are promising new modalities that are transitioning from research into clinical
practice. Alternatively, one might also interfere with the transcriptional
machinery. Selective blocking of the messenger RNA responsible for carrying the
sequence information of the targeted protein by using so called antisense
oligonucleotides, small interfering RNAs, or micro RNAs can result in a
decreased synthesis of the protein. Appropriately designed oligonucleotides can
also enhance protein synthesis or lead to an alteration of the sequence to
synthesize for a given protein. Finally, we might also target the epigenetic
regulatory machinery, which is in charge of unpacking the DNA double helix from
its storage form and making it available for transcription. This interference
typically leads to a more complex change, the parallel modulation of the level
of several proteins at the same time.