Potent D-peptide inhibitors of HIV-1 entry

Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16828-33. doi: 10.1073/pnas.0708109104. Epub 2007 Oct 17.


During HIV-1 entry, the highly conserved gp41 N-trimer pocket region becomes transiently exposed and vulnerable to inhibition. Using mirror-image phage display and structure-assisted design, we have discovered protease-resistant D-amino acid peptides (D-peptides) that bind the N-trimer pocket with high affinity and potently inhibit viral entry. We also report high-resolution crystal structures of two of these D-peptides in complex with a pocket mimic that suggest sources of their high potency. A trimeric version of one of these peptides is the most potent pocket-specific entry inhibitor yet reported by three orders of magnitude (IC(50) = 250 pM). These results are the first demonstration that D-peptides can form specific and high-affinity interactions with natural protein targets and strengthen their promise as therapeutic agents. The D-peptides described here address limitations associated with current L-peptide entry inhibitors and are promising leads for the prevention and treatment of HIV/AIDS.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Crystallography, X-Ray
  • HIV Envelope Protein gp41 / chemistry
  • HIV-1 / drug effects*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Library
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Structure, Quaternary
  • Sequence Alignment
  • Surface Plasmon Resonance
  • Virus Internalization / drug effects*


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

Associated data

  • PDB/2R3C
  • PDB/2R5B
  • PDB/2R5D