Potent D-peptide inhibitors of HIV-1 entry

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 43; pp. 16828 - 16833
• Main Authors: Welch, Brett D, VanDemark, Andrew P, Heroux, Annie, Hill, Christopher P, Kay, Michael S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-10-2007; National Acad Sciences
• Subjects: AFFINITY; Amino Acid Sequence; Amino acids; Anti-HIV Agents - pharmacology; Antioxidants; Bacteriophages; Biological Sciences; Cell Line; Cell membranes; CRYSTAL STRUCTURE; Crystallography, X-Ray; DESIGN; DRUGS; HIV; HIV 1; HIV Envelope Protein gp41 - chemistry; HIV-1 - drug effects; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Hydrogen bonds; Inhibitory concentration 50; Libraries; MATERIALS SCIENCE; Models, Molecular; Molecular Sequence Data; Monomers; national synchrotron light source; Peptide Library; PEPTIDES; Peptides - chemistry; Peptides - pharmacology; Protein Structure, Quaternary; PROTEINS; Sequence Alignment; Surface Plasmon Resonance; TARGETS; Trimers; Virus Internalization - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0708109104

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 (IC₅₀ = 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.