Potent D-peptide inhibitors of HIV-1 entry

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 h...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-10, Vol.104 (43), p.16828-16833
Main Authors: Welch, Brett D, VanDemark, Andrew P, Heroux, Annie, Hill, Christopher P, Kay, Michael S
Format: Article
Language:English
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
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Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0708109104