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Updated: Jul 10, 2026

Peptide-based Identification of Functional Motifs and their Binding Partners
Published on: June 30, 2013
Potent D-peptide inhibitors of HIV-1 entry
Brett D Welch1, Andrew P VanDemark, Annie Heroux
1Department of Biochemistry, University of Utah, Emma Eccles Jones Medical Research Building, 15 North Medical Drive East, Salt Lake City, UT 84112-5650, USA.
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.
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