Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide

Cell. 2007 Apr 20;129(2):263-75. doi: 10.1016/j.cell.2007.02.042.


A variety of molecules in human blood have been implicated in the inhibition of HIV-1. However, it remained elusive which circulating natural compounds are most effective in controlling viral replication in vivo. To identify natural HIV-1 inhibitors we screened a comprehensive peptide library generated from human hemofiltrate. The most potent fraction contained a 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of alpha1-antitrypsin, the most abundant circulating serine protease inhibitor. We found that VIRIP inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. Further analysis demonstrated that VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide and showed that a few amino acid changes increase its antiretroviral potency by two orders of magnitude. Thus, as a highly specific natural inhibitor of the HIV-1 gp41 fusion peptide, VIRIP may lead to the development of another class of antiretroviral drugs.

MeSH terms

  • Amino Acid Sequence
  • Blood Proteins / chemistry
  • Blood Proteins / metabolism
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / metabolism*
  • HIV Fusion Inhibitors / chemistry
  • HIV Fusion Inhibitors / metabolism
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / chemistry
  • HIV-1 / drug effects*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Virus Internalization / drug effects*
  • Virus Replication
  • alpha 1-Antitrypsin / chemistry
  • alpha 1-Antitrypsin / metabolism
  • alpha 1-Antitrypsin / pharmacology*


  • Blood Proteins
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • VIRIP peptide, human
  • alpha 1-Antitrypsin

Associated data

  • PDB/2JNR