SC29EK, a peptide fusion inhibitor with enhanced alpha-helicity, inhibits replication of human immunodeficiency virus type 1 mutants resistant to enfuvirtide

Antimicrob Agents Chemother. 2009 Mar;53(3):1013-8. doi: 10.1128/AAC.01211-08. Epub 2008 Dec 29.

Abstract

Peptides derived from the alpha-helical domains of human immunodeficiency virus (HIV) type 1 (HIV-1) gp41 inhibit HIV-1 fusion to the cell membrane. Enfuvirtide (T-20) is a peptide-based drug that targets the step of HIV fusion, and as such, it effectively suppresses the replication of HIV-1 strains that are either wild type or resistant to multiple reverse transcriptase and/or protease inhibitors. However, HIV-1 variants with T-20 resistance have emerged; therefore, the development of new and potent inhibitors is urgently needed. We have developed a novel HIV fusion inhibitor, SC34EK, which is a gp41-derived 34-amino-acid peptide with glutamate (E) and lysine (K) substitutions on its solvent-accessible site that stabilize its alpha-helicity. Importantly, SC34EK effectively inhibits the replication of T-20-resistant HIV-1 strains as well as wild-type HIV-1. In this report, we introduce SC29EK, a 29-amino-acid peptide that is a shorter variant of SC34EK. SC29EK blocked the replication of T-20-resistant HIV-1 strains and maintained antiviral activity even in the presence of high serum concentrations (up to 50%). Circular dichroism analysis revealed that the alpha-helicity of SC29EK was well maintained, while that of the parental peptide, C29, which showed moderate and reduced inhibition of wild-type and T-20-resistant HIV-1 strains, was lower. Our results show that the alpha-helicity in a peptide-based fusion inhibitor is a key factor for activity and enables the design of short peptide inhibitors with improved pharmacological properties.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / drug effects
  • Circular Dichroism
  • Drug Resistance, Viral / drug effects*
  • Drug Resistance, Viral / genetics
  • Enfuvirtide
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors / chemistry*
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / physiology
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Peptide Fragments
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protein Structure, Secondary / genetics
  • Virus Replication / drug effects*

Substances

  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • Peptides
  • SC29EK peptide
  • Enfuvirtide