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An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule

Kessl, Jacques J. and Eidahl, Jocelyn O. and Shkriabai, Nikolozi and Zhao, Zhuojun and McKee, Christopher J. and Hess, Sonja and Burke, Terrence R., Jr. and Kvaratskhelia, Mamuka (2009) An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule. Molecular Pharmacology, 76 (4). pp. 824-832. ISSN 0026-895X. https://resolver.caltech.edu/CaltechAUTHORS:20091013-093448460

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Abstract

HIV-1 integrase (IN) is a validated target for developing antiretroviral inhibitors. Using affinity acetylation and mass spectrometric (MS) analysis, we previously identified a tetra-acetylated inhibitor (2E)-3-[3,4-bis(acetoxy)phenyl]-2-propenoate-N-[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propenyl]-L-serine methyl ester; compound 1] that selectively modified Lys173 at the IN dimer interface. Here we extend our efforts to dissect the mechanism of inhibition and structural features that are important for the selective binding of compound 1. Using a subunit exchange assay, we found that the inhibitor strongly modulates dynamic interactions between IN subunits. Restricting such interactions does not directly interfere with IN binding to DNA substrates or cellular cofactor lens epithelium-derived growth factor, but it compromises the formation of the fully functional nucleoprotein complex. Studies comparing compound 1 with a structurally related IN inhibitor, the tetra-acetylated-chicoric acid derivative (2R,3R)-2,3-bis[[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propen-1-yl]oxy]-butanedioic acid (compound 2), indicated striking mechanistic differences between these agents. The structures of the two inhibitors differ only in their central linker regions, with compounds 1 and 2 containing a single methyl ester group and two carboxylic acids, respectively. MS experiments highlighted the importance of these structural differences for selective binding of compound 1 to the IN dimer interface. Moreover, molecular modeling of compound 1 complexed to IN identified a potential inhibitor binding cavity and provided structural clues regarding a possible role of the central methyl ester group in establishing an extensive hydrogen bonding network with both interacting subunits. The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1124/mol.109.058883DOIArticle
http://molpharm.aspetjournals.org/cgi/content/abstract/76/4/824PublisherArticle
ORCID:
AuthorORCID
Hess, Sonja0000-0002-5904-9816
Additional Information:U.S. Government work not protected by U.S. copyright. Received June 25, 2009; accepted July 28, 2009. First published on July 28, 2009; DOI: 10.1124/mol.109.058883. HIV-1 IN Monoclonal Antibody (2C11) was obtained from Dr. Dag E. Helland through the AIDS Research and Reference Reagent Program, Division of AIDS, the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. This work was supported by National Institutes of Health National Institute of Allergy and Infectious Diseases [Grants AI062520, AI077341]; and by the Intramural Research Programs of the National Institutes of Health Center for Cancer Research, the National Institutes of Health National Cancer Institute, and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Experiments by S.H. were conducted at the Proteomics and Mass Spectrometry Facility of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
Funders:
Funding AgencyGrant Number
National Institute of Allergy and Infectious DiseasesAI062520
National Institute of Allergy and Infectious DiseasesAI077341
National Cancer InstituteUNSPECIFIED
National Institute of Diabetes and Digestive and Kidney DiseasesUNSPECIFIED
Issue or Number:4
Record Number:CaltechAUTHORS:20091013-093448460
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20091013-093448460
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16299
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:22 Oct 2009 18:41
Last Modified:03 Oct 2019 01:09

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