An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule
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 (2 E )-3-[3,4-bis(acetoxy)phenyl]-2-propenoate- N -[(2 E )-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-...
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Published in | Molecular pharmacology Vol. 76; no. 4; pp. 824 - 832 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.10.2009
The American Society for Pharmacology and Experimental Therapeutics |
Subjects | |
Online Access | Get full text |
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Summary: | 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 (2 E )-3-[3,4-bis(acetoxy)phenyl]-2-propenoate- N -[(2 E )-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 (2 R ,3 R )-2,3-bis[[(2 E )-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. |
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Bibliography: | 1Current affiliation: Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland. |
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.109.058883 |