Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket

Cell. 1999 Oct 1;99(1):103-15. doi: 10.1016/s0092-8674(00)80066-5.


The HIV-1 gp41 protein promotes viral entry by mediating the fusion of viral and cellular membranes. A prominent pocket on the surface of a central trimeric coiled coil within gp41 was previously identified as a potential target for drugs that inhibit HIV-1 entry. We designed a peptide, IQN17, which properly presents this pocket. Utilizing IQN17 and mirror-image phage display, we identified cyclic, D-peptide inhibitors of HIV-1 infection that share a sequence motif. A 1.5 A cocrystal structure of IQN17 in complex with a D-peptide, and NMR studies, show that conserved residues of these inhibitors make intimate contact with the gp41 pocket. Our studies validate the pocket per se as a target for drug development. IQN17 and these D-peptide inhibitors are likely to be useful for development and identification of a new class of orally bioavailable anti-HIV drugs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • CHO Cells
  • Cricetinae
  • Crystallography
  • HIV Envelope Protein gp41 / chemistry*
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / chemistry*
  • Inovirus
  • Magnetic Resonance Spectroscopy
  • Membrane Fusion / drug effects
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Protein Structure, Secondary
  • Protein Structure, Tertiary


  • Anti-HIV Agents
  • HIV Envelope Protein gp41
  • Peptides

Associated data

  • PDB/1CZQ