title: Potent D-peptide inhibitors of HIV-1 entry.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Utah, Emma Eccles Jones Medical Research Building, 15 North Medical Drive East, Salt Lake City, UT 84112-5650, USA.
authors.forename: Brett D
authors.initials: BD
authors.lastname: Welch
authors.forename: Andrew P
authors.initials: AP
authors.lastname: VanDemark
authors.forename: Annie
authors.initials: A
authors.lastname: Heroux
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hill
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kay
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D020349:Surface Plasmon Resonance; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D019151:Peptide Library; D010455:Peptides