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Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target

Chan, David C. and Chutkowski, C. T. and Kim, Peter-S (1998) Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proceedings of the National Academy of Sciences of the United States of America, 95 (26). pp. 15613-15617. ISSN 0027-8424. PMCID PMC28092. http://resolver.caltech.edu/CaltechAUTHORS:20170707-135940010

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Abstract

Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.95.26.15613DOIArticle
http://www.pnas.org/content/95/26/15613PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC28092/PubMed CentralArticle
Additional Information:© 1998 National Academy of Sciences. Contributed by Peter S. Kim, October 23, 1998. We are grateful to Michael Burgess, James Pang, and Roberta Moro for peptide synthesis and mass spectrometry support. We also thank Dr. Benjamin Chen for providing reagents and helpful advice on viral infection assays, Drs. Nathaniel Landau and Monty Krieger for providing cell lines, Dr. Michael Root for helpful advice regarding data analysis, and the Kim lab for stimulating discussions and comments on the manuscript. D.C.C. was supported by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund for Medical Research and is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences. This research was funded by the National Institutes of Health (PO1 GM56552). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funders:
Funding AgencyGrant Number
Jane Coffin Childs Memorial Fund for Medical ResearchUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
NIHPO1 GM56552
PubMed Central ID:PMC28092
Record Number:CaltechAUTHORS:20170707-135940010
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170707-135940010
Official Citation:David C. Chan, Christine T. Chutkowski, and Peter S. Kim Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target PNAS 1998 95 (26) 15613-15617; doi:10.1073/pnas.95.26.15613
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:78866
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Jul 2017 17:26
Last Modified:10 Jul 2017 17:26

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