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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010A New Synthetic Strategy for Novel AntibacterialHybrid Drug-Like MoleculesI. Lapidot 1,2 , G. Zats 1,2 , A. Albeck 2 , G. Gellerman 1 , and S. Shatzmiller 11 Department of Biological Chemistry, Ariel, 40700, Ariel University Center of Samaria,Israel; 2 Department of Chemistry, Ramat-Gan, 52900, Bar-Ilan University, IsraelIntroductionThe phenomenon of antibiotic resistant bacteria is a global problem which is hard to dealwith and is getting worse. Therefore, it is necessary to discover new antibiotics.Antibacterial peptides (AMPs) are the effector molecules of innate immunity. Generallythey contain 15–45 amino acid residues. Most antibacterial peptides share several commonfeatures i.e.: positive charge domains (i.e. contain lysines and arginines), hydrophobicamino acids (i.e. contain valine and phenyl alanine) and amphipathic structures.Furthermore, most native antimicrobial peptides have no cytolytic activity against normalmammalian cells at their minimal antimicrobial inhibitory concentration (MIC) [1].Various known and novel scaffolds are, among others, 1, 4-Dihydropyridines [2,3] andBenzodiazepines [4,5]. They are abundant source of molecules with proven biologicalactivity. The present research refers to the phenomenon of pharmacokinetics as well aspharmacodynamics in pharmacologic activity, namely the modification that extends use ofexisting medicines. In particular, the changes of the medications which are known andusable. For medicines known, this change is achieved by combining them with peptidesequences (based on Dermaseptine fragments [6,7]), in order to produce hybrid drug likemolecules with better desired potential therapeutic features.Results and DiscussionThe advantage of the AMPs over conventional antibiotics is their operating mechanism,which refers to the interaction between the bacteria's membrane and the peptide. This factmakes it much more difficult for the microorganisms to develop resistancy to AMPs.Bacteria’s ability to become resistant to antibiotics presents an urgent need to developvarious tools to supplement the current available antibiotic treatments. However, thepharmaceutical industry shows interest in Synthetic Antimicrobial Peptidomimetics(SAMPs) and not in AMPs. The reason for that preference is probably because of the highmolecular weight of the natural polypeptides, low stability in the blood serum, lowselectivity and the high cost [8,9].We have identified in the amino-acids sequence of the antibacterial polypeptide fromfrog skins, Dermaseptin-S1 (Figure 1) a short sequence of 5 amino-acids (via the Linearepitope system) present in the natural product, namely KTMLK ([1a] Lys-Thr-Met-Leu-Lys). This was found to have bactericidal activity, i.e. killing Gram negative as well asGram positive bacteria. Linear epitopes based on [1a] were prepared in which the aminoacidsT and M as well as L were replaced by other hydrophobic amino acids. All show thesame biological activity.S4=ALLGAAADTISQGTQWMTLLKKVLKAAAKALNAVLVGANAS1=ALWKTMLKKLGTMALHAGKAAFig. 1. Dermaseptine sequence amino-acids (S1 & S4).As a result of all these facts we designed novel peptidomimetics compounds that contain1,4-Dihydropyridines (IL) and Benzodiazepines (GZ) (scaffolds- Figure 2) bound to AMPssequence that derived from the Dermaseptine skin – all this unit together constitute Hybriddrug-like molecule.There are many suggestions for mechanisms explaining the bactericidal nature of thesemore than 800 isolated natural antimicrobial peptides [8-10]. However, one of thesemechanisms is based on the idea that positively charged amino acids like Lysine, Argininepresent in the antimicrobial peptides in large abundance can replace metal cations attachedto phospholipids – lipopolysacchrides [11] and peptide-glycans – Teichoic acid [12] layersforming the essential supra-molecular structures based on coordination with metal cations236