## 3 Discussion  
In this study, we investigated the potential activity of 75 peptide-based drugs for the \(\beta\)-sheet breaker mechanism. In order to increase the biocompatibility for different methods of administration, we started with five peptides based on the A\(\beta_{(15-20)}\) sequence to which 14 different organic compounds were attached at the N-terminal of the sequence.  
Following the preliminary analysis of different pharmacological features, the peptides with the best biocompatibility regarding intranasal, gastrointestinal and BBB administration were based on the sequence \({}^{17}\)LVFF [20] and \({}^{16}\)KLVF [19]. In addition, we chose to investigate the nicotinic acid-peptide conjugate because it can regulate different forms of neuroprotective actions. Furthermore, it was noticed that that the addition of NA to the peptide molecule increases the affinity for Family AG protein-coupled receptor and for proteases, which could also improve the cognitive functions in [PERSON]'s disease.  
Moreover, according to Flexible Alignment data, the peptide conjugates NA-\({}^{17}\)LVFF [20] and NA-\({}^{16}\)KLVF [19] developed the entanglement process, and hence they could improve the process of the \(\beta\)-sheet breaker mechanism. In addition, the molecular pathway through which peptides interact with A\(\beta_{(1-42)}\) fibrils seems to be at the top or at the bottom of the fibril. Hence, the process of the \(\beta\)-sheet breaker could occur. Moreover, if a combination between \({}^{16}\)KLVF [19] and NA-\({}^{16}\)KLVF [19] is used in a therapeutic pathway, where the first peptide is attached at the top and the peptide-based drug is at the end of the fibril, fibrillar formation obstruction could ensue. The van der Waals interactions between \({}^{16}\)KLVF [19] and A\(\beta_{(1-42)}\) fibrils show that the peptide might possess the ability to destabilize the structures.  
Following preliminary investigation, four conjugates from the investigated line-up were synthetized using solid-phase peptide synthesis. Tandem mass spectrometry of the newly designed peptides showed, following the CID, weaker bonds between phenylalanine residues, which result in the formation of the \({}^{17}\)LVF [18] fragment. In the case of the \({}^{16}\)KLVF [19] peptide, the spectrum did not evidence any fragmentation. These interesting data suggest that, in the presence of a protease, the peptide cleavage is not possible. This could significantly improve the neuroprotective action. Therefore, the peptide \({}^{16}\)KLVF [19] could attach at the A\(\beta_{(1-42)}\) monomer and fibrils, inhibiting fibril formation and improving the \(\beta\)-sheet breaker mechanism, with the release of NA to improve neuroprotective functions.  
Consequently, CD spectra show that \({}^{16}\)KLVF [19] linked to NA drastically increases the proportion of random coil conformers. This suggests that the NA-\({}^{16}\)KLVF [19] confirms docking simulations and, therefore, could improve the \(\beta\)-sheet breaker mechanism. Moreover, the entanglement process can also be effective.  
The novelty of our work is represented by the study of new combinations between A\(\beta_{(15-20)}\) and various organic acids, as well as a unique computational estimate of these properties. However, it is necessary to further investigate the in vitro and in vivo properties of peptide-based drugs. In addition, this work focused on the main features of these beta-sheet breaker molecules when the main design was approached. Moreover, a recent study showed that the \({}^{1}\)FRSAPFIE [8] (FRS) octapeptide could act as a drug delivery system [48]. Hence, a system formed by our beta-sheet breaker peptides and FRS might act as a transporter (e.g., intranaxally) for our final purpose: the disruption of amyloid beta fibril formation.