Journal of Combinatorial Chemistry · 2004 · 37 citations · 27 references
PharmacyMedicinal ChemistryPharmacologyDrug DesignDrug DiscoveryLead OptimizationAntimicrobial PeptidesCombinatorial SynthesisLibrary DesignNatural Product Drug DiscoveryNatural Product-based Drug DesignPotency OptimizationAntibacterial PropertiesCombinatorial Cyclic Peptide SynthesisCombinatorial Library ScreeningCyclic Peptide DesignCyclic Peptide LibrariesDrug-resistant PathogensNovel Antibacterial Drug DiscoveryPeptide Library Design
A previously developed method for cyclic peptide synthesis was demonstrated to be able to provide convenient access to large combinatorial libraries of analogues, and this methodology was applied to the optimization of natural product cyclic decapeptides. Using this method, a 192-member library was designed and successfully constructed on the basis of the natural products tyrocidines, streptocidins, and loloatins to increase the therapeutic indices of these antibiotics. Library screening identified nine analogues whose therapeutic indices were increased by up to 90-fold in comparison to the natural products. Three of these analogues showed significant increase in antibacterial potency and concurrent drastic decrease in hemolytic activity. Since the natural products target the bacterial cell wall, the newly discovered analogues are promising leads for drug development against drug-resistant bacteria.
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Margitta Dathe, Torsten Wieprecht, Heike Nikolenko et al. · FEBS Letters · 1997 · 409 citations · Full text
Gramicidin S and its use in the Treatment of Infected Wounds
G. F. Gause, M G Brazhnikova · Nature · 1944 · 299 citations