Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action
Identifieur interne : 001448 ( Main/Exploration ); précédent : 001447; suivant : 001449Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action
Auteurs : A. Hombrouck [Belgique] ; A. Hantson [Belgique] ; B. Van Remoortel [Belgique] ; M. Michiels [Belgique] ; J. Vercammen [Belgique] ; D. Rhodes [Australie] ; V. Tetz [Russie] ; Y. Engelborghs [Belgique] ; F. Christ [Belgique] ; Z. Debyser [Belgique] ; M. Witvrouw [Belgique]Source :
- Journal of Antimicrobial Chemotherapy [ 0305-7453 ] ; 2007-06.
Abstract
Objectives We have previously identified the pyranodipyrimidines (PDPs) as a new class of integrase (IN) inhibitors. The most potent congener V-165 inhibits HIV-1 integration at low micromolar concentrations by inhibiting the binding of IN to the DNA. As part of pre-clinical studies with PDP, we wanted to investigate HIV resistance development against V-165 and to further characterize the physicochemical properties of the compound. Methods We selected PDP-resistant HIV-1 strains by growing the virus in the presence of increasing concentrations of V-165. The selected strains were analysed genotypically and phenotypically. Mutant IN enzymes were generated and evaluated in an enzymatic oligonucleotide-based assay for their activity and sensitivity to the different IN inhibitors. In addition, the antiviral effect of the compound on viral entry and integration was measured using quantitative PCR. Results Numerous mutations were detected in the RT, IN and env genes of the virus selected in the presence of V-165. Although V-165 inhibited integration in vivo as indicated by a decrease in the number of integrated proviruses, the compound also inhibited viral entry at a concentration of 19 M. V-165 was poorly recovered from human hepatic microsomal matrix and 1 BSA. Conclusions These data point to a multimodal mechanism of action. A quest for derivatives of V-165 that specifically target IN should be pursued.
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DOI: 10.1093/jac/dkm101
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Vercammen</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Biomolecular Dynamics, Katholieke Universiteit Leuven, Leuven, Flanders</wicri:regionArea><wicri:noRegion>Flanders</wicri:noRegion></affiliation></author><author><name sortKey="Rhodes, D" sort="Rhodes, D" uniqKey="Rhodes D" first="D." last="Rhodes">D. Rhodes</name><affiliation wicri:level="1"><country xml:lang="fr">Australie</country><wicri:regionArea>Avexa Limited, Richmond, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Tetz, V" sort="Tetz, V" uniqKey="Tetz V" first="V." last="Tetz">V. 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Christ</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Molecular Virology and Gene Therapy, Katholieke Universiteit Leuven, Leuven, Flanders</wicri:regionArea><wicri:noRegion>Flanders</wicri:noRegion></affiliation></author><author><name sortKey="Debyser, Z" sort="Debyser, Z" uniqKey="Debyser Z" first="Z." last="Debyser">Z. 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Witvrouw</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Molecular Virology and Drug Discovery, Katholieke Universiteit Leuven, Leuven, Flanders</wicri:regionArea><wicri:noRegion>Flanders</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Interdisciplinary Research Center, Katholieke Universiteit Leuven Campus Kortrijk, Kortrijk, Flanders</wicri:regionArea><wicri:noRegion>Flanders</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Belgique</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Antimicrobial Chemotherapy</title><idno type="ISSN">0305-7453</idno><idno type="eISSN">1460-2091</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2007-06">2007-06</date><biblScope unit="volume">59</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1084">1084</biblScope><biblScope unit="page" to="1095">1095</biblScope></imprint><idno type="ISSN">0305-7453</idno></series><idno type="istex">FF5043131C654E8AC0196D54A115C2BEA3FFE505</idno><idno type="DOI">10.1093/jac/dkm101</idno><idno type="ArticleID">dkm101</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0305-7453</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Objectives We have previously identified the pyranodipyrimidines (PDPs) as a new class of integrase (IN) inhibitors. The most potent congener V-165 inhibits HIV-1 integration at low micromolar concentrations by inhibiting the binding of IN to the DNA. As part of pre-clinical studies with PDP, we wanted to investigate HIV resistance development against V-165 and to further characterize the physicochemical properties of the compound. Methods We selected PDP-resistant HIV-1 strains by growing the virus in the presence of increasing concentrations of V-165. The selected strains were analysed genotypically and phenotypically. Mutant IN enzymes were generated and evaluated in an enzymatic oligonucleotide-based assay for their activity and sensitivity to the different IN inhibitors. In addition, the antiviral effect of the compound on viral entry and integration was measured using quantitative PCR. Results Numerous mutations were detected in the RT, IN and env genes of the virus selected in the presence of V-165. Although V-165 inhibited integration in vivo as indicated by a decrease in the number of integrated proviruses, the compound also inhibited viral entry at a concentration of 19 M. V-165 was poorly recovered from human hepatic microsomal matrix and 1 BSA. Conclusions These data point to a multimodal mechanism of action. A quest for derivatives of V-165 that specifically target IN should be pursued.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>Russie</li></country></list><tree><country name="Belgique"><noRegion><name sortKey="Hombrouck, A" sort="Hombrouck, A" uniqKey="Hombrouck A" first="A." last="Hombrouck">A. Hombrouck</name></noRegion><name sortKey="Christ, F" sort="Christ, F" uniqKey="Christ F" first="F." last="Christ">F. Christ</name><name sortKey="Debyser, Z" sort="Debyser, Z" uniqKey="Debyser Z" first="Z." last="Debyser">Z. Debyser</name><name sortKey="Debyser, Z" sort="Debyser, Z" uniqKey="Debyser Z" first="Z." last="Debyser">Z. Debyser</name><name sortKey="Engelborghs, Y" sort="Engelborghs, Y" uniqKey="Engelborghs Y" first="Y." last="Engelborghs">Y. Engelborghs</name><name sortKey="Hantson, A" sort="Hantson, A" uniqKey="Hantson A" first="A." last="Hantson">A. Hantson</name><name sortKey="Hantson, A" sort="Hantson, A" uniqKey="Hantson A" first="A." last="Hantson">A. Hantson</name><name sortKey="Hombrouck, A" sort="Hombrouck, A" uniqKey="Hombrouck A" first="A." last="Hombrouck">A. Hombrouck</name><name sortKey="Michiels, M" sort="Michiels, M" uniqKey="Michiels M" first="M." last="Michiels">M. Michiels</name><name sortKey="Van Remoortel, B" sort="Van Remoortel, B" uniqKey="Van Remoortel B" first="B." last="Van Remoortel">B. Van Remoortel</name><name sortKey="Vercammen, J" sort="Vercammen, J" uniqKey="Vercammen J" first="J." last="Vercammen">J. Vercammen</name><name sortKey="Witvrouw, M" sort="Witvrouw, M" uniqKey="Witvrouw M" first="M." last="Witvrouw">M. Witvrouw</name><name sortKey="Witvrouw, M" sort="Witvrouw, M" uniqKey="Witvrouw M" first="M." last="Witvrouw">M. Witvrouw</name><name sortKey="Witvrouw, M" sort="Witvrouw, M" uniqKey="Witvrouw M" first="M." last="Witvrouw">M. Witvrouw</name></country><country name="Australie"><noRegion><name sortKey="Rhodes, D" sort="Rhodes, D" uniqKey="Rhodes D" first="D." last="Rhodes">D. Rhodes</name></noRegion></country><country name="Russie"><noRegion><name sortKey="Tetz, V" sort="Tetz, V" uniqKey="Tetz V" first="V." last="Tetz">V. Tetz</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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