De novo design of selective antibiotic peptides by incorporation of unnatural amino acids

Rickey P. Hicks, Jayendra B. Bhonsle, Divakaramenon Venugopal, Brandon W. Koser, Alan J. Magill

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

The evolution of drug-resistant bacteria is one of the most critical problems facing modern medicine and requires the development of new drugs that exhibit their antibacterial activity via novel mechanisms of action. One potential source of new drugs could be the naturally occurring peptides that exhibit antimicrobial activity via membrane disruption. To develop antimicrobial peptides exhibiting increased potency and selectivity against Gram positive, Gram negative, and Mycobacterium bacteria coupled with reduced hemolytic activity, peptides containing unnatural amino acids have been designed, synthesized, and evaluated. These compounds were designed on the basis of the electrostatic surface potential maps derived from the NMR determined SDS and DPC micelle-bound conformations of (Ala8,13,18)magainin-2 amide. Unnatural amino acids were incorporated into the polypeptide backbone to control the structural and physicochemical properties of the peptides to introduce organism selectivity and potency. The methods and results of this investigation are described below.

Original languageEnglish (US)
Pages (from-to)3026-3036
Number of pages11
JournalJournal of Medicinal Chemistry
Volume50
Issue number13
DOIs
StatePublished - Jun 28 2007

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Hicks, R. P., Bhonsle, J. B., Venugopal, D., Koser, B. W., & Magill, A. J. (2007). De novo design of selective antibiotic peptides by incorporation of unnatural amino acids. Journal of Medicinal Chemistry, 50(13), 3026-3036. https://doi.org/10.1021/jm061489v