Bivalent HIV-1 fusion inhibitors based on peptidomimetics

Bioorg Med Chem. 2020 Dec 15;28(24):115812. doi: 10.1016/j.bmc.2020.115812. Epub 2020 Oct 9.

Abstract

Membrane fusion is a valid target for inhibition of HIV-1 replication. A 34-mer fragment peptide (C34), which is contained in the HIV-1 envelope protein gp41, has significant anti-HIV activity. Previously, a dimeric derivative of C34 linked by a disulfide bridge at its C-terminus was found to have more potent anti-HIV activity than the C34 peptide monomer. To date, several peptidomimetic small inhibitors have been reported, but most have lower potency than peptide derivatives related to C34. In the present study we applied this dimerization concept to these peptidomimetic small inhibitors and designed several bivalent peptidomimetic HIV-1 fusion inhibitors. The importance of the length of linkers crosslinking two peptidomimetic compounds was demonstrated and several potent bivalent inhibitors containing tethered peptidomimetics were produced.

Keywords: Anti-HIV-1 activity; Bivalent fusion inhibitor; Peptidomimetic; gp41.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dimerization
  • Disulfides / chemistry
  • Drug Design
  • HIV Envelope Protein gp41 / chemistry*
  • HIV Envelope Protein gp41 / metabolism
  • HIV Fusion Inhibitors / chemistry*
  • HIV Fusion Inhibitors / metabolism
  • HIV Fusion Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / metabolism
  • Humans
  • Peptides / chemistry
  • Peptidomimetics*
  • Polyethylene Glycols / chemistry

Substances

  • Disulfides
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptides
  • Peptidomimetics
  • gp41 protein, Human immunodeficiency virus 1
  • Polyethylene Glycols