Design, synthesis, and biological evaluation of stable β6.3-Helices: Discovery of non-hemolytic antibacterial peptides

Damodara N. Reddy, Sukrit Singh, Chris M.W. Ho, Janki Patel, Paul Schlesinger, Stephen Rodgers, Allan Doctor, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)8-NHCH2CH2OH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)16-OtBu channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A.

Original languageEnglish
Pages (from-to)193-210
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume149
DOIs
StatePublished - Apr 10 2018

Keywords

  • Antibiotic
  • Azaproline foldamers
  • Gramicidin
  • Liposomes and beta-helices
  • RBC hemolysis

Fingerprint Dive into the research topics of 'Design, synthesis, and biological evaluation of stable β<sup>6.3</sup>-Helices: Discovery of non-hemolytic antibacterial peptides'. Together they form a unique fingerprint.

Cite this