2000
DOI: 10.1073/pnas.200139397
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HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase

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Cited by 299 publications
(290 citation statements)
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References 35 publications
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“…L-870,810 is also the prototype of a structural class of 8-hydroxy-1,6-naphthyridine-7-carboxamides, which provide a previously uncharacterized pharmacophore for inhibitor design. Like previously described diketo acids, the 8-hydroxy-1,6-naphthyridine-7-carboxamides selectively inhibit integrasemediated strand transfer (5,7). Although these inhibitors are mechanistically indistinguishable, we have shown that distinct resistance profiles can be obtained with homologous naphthyridine and diketo acid analogs, providing the proof of concept and rationale for designing integrase inhibitors with the potential for unique and nonoverlapping resistance.…”
Section: Discussionsupporting
confidence: 59%
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“…L-870,810 is also the prototype of a structural class of 8-hydroxy-1,6-naphthyridine-7-carboxamides, which provide a previously uncharacterized pharmacophore for inhibitor design. Like previously described diketo acids, the 8-hydroxy-1,6-naphthyridine-7-carboxamides selectively inhibit integrasemediated strand transfer (5,7). Although these inhibitors are mechanistically indistinguishable, we have shown that distinct resistance profiles can be obtained with homologous naphthyridine and diketo acid analogs, providing the proof of concept and rationale for designing integrase inhibitors with the potential for unique and nonoverlapping resistance.…”
Section: Discussionsupporting
confidence: 59%
“…1) that prevent integration and viral replication in cell culture provided the first proof of concept for HIV-1 integrase inhibitors as antiviral agents. These compounds were shown to act specifically as inhibitors of the integrase strand transfer reaction by virtue of their ability to bind selectively to the enzyme complexed with the viral (or donor) DNA and compete with the host (or target) DNA substrate (7,8). The critical diketo carboxylate pharmacophore interacts with critical divalent metal ions in the active site (8) and mutations that engender resistance to these prototype inhibitors (5,9), and closely related analogs map to the integrase active site proximal to residues that coordinate divalent metals (D66, D116, and E152).…”
mentioning
confidence: 99%
“…Binding of each compound was saturable, not cooperative (Hill coefficent Ϸ1), and required both IN and DNA. As reported (20), binding correlated with activity of the strand transfer complex: (i) binding was detected with full-length IN and not with truncated enzymes competent to catalyze disintegration but not strand transfer, and (ii) binding was detected when IN was assembled onto viral DNA ends and not nonspecific sequence or single-stranded DNAs (data not shown). In saturation binding studies using the U5 long terminal repeat DNA sequence, dissociation constants of 15 and 5 nM were determined for compounds I and II, respectively (Fig.…”
Section: Dka Binding Correlates With Assembly Of An In Complex Competentsupporting
confidence: 69%
“…The inhibitor 5CITEP [1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)-propenone] also binds within the IN active site (19). In the crystal structure of the core domain of IN (amino acids 50-212) with 5CITEP, the inhibitor contacts IN residues that are identical or close to those predicted to be important for the DKAs on the basis of resistance.Previous studies have shown that the binding of DKA inhibitors requires that IN be assembled into a nucleoprotein complex competent to catalyze strand transfer and that binding of the inhibitor and the target DNA substrate are mutually exclusive (20). These studies suggest a biochemical basis for the strand transfer selectivity of these inhibitors.…”
mentioning
confidence: 86%
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