Detailed mechanistic insights into HIV-1 sensitivity to three generations of fusion inhibitors Academic Article uri icon

Overview

MeSH Major

  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • HIV-1
  • Peptide Fragments
  • Peptides

abstract

  • Peptides based on the second heptad repeat (HR2) of viral class I fusion proteins are effective inhibitors of virus entry. One such fusion inhibitor has been approved for treatment of human immunodeficiency virus-1 (T20, enfuvirtide). Resistance to T20 usually maps to the peptide binding site in HR1. To better understand fusion inhibitor potency and resistance, we combined virological, computational, and biophysical experiments with comprehensive mutational analyses and tested resistance to T20 and second and third generation inhibitors (T1249 and T2635). We found that most amino acid substitutions caused resistance to the first generation peptide T20. Only charged amino acids caused resistance to T1249, and none caused resistance to T2635. Depending on the drug, we can distinguish four mechanisms of drug resistance: reduced contact, steric obstruction, electrostatic repulsion, and electrostatic attraction. Implications for the design of novel antiviral peptide inhibitors are discussed.

publication date

  • September 25, 2009

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2785381

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.004416

PubMed ID

  • 19617355

Additional Document Info

start page

  • 26941

end page

  • 50

volume

  • 284

number

  • 39