Small-molecule inhibition of HIV-1 Vif. Export

@article{citeulike:3329302, abstract = {The HIV-1 protein Vif, essential for in vivo viral replication, targets the human DNA-editing enzyme, APOBEC3G (A3G), which inhibits replication of retroviruses and hepatitis B virus. As Vif has no known cellular homologs, it is an attractive, yet unrealized, target for antiviral intervention. Although zinc chelation inhibits Vif and enhances viral sensitivity to A3G, this effect is unrelated to the interaction of Vif with A3G. We identify a small molecule, RN-18, that antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degradation. RN-18 enhances Vif degradation only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome. These results demonstrate that the HIV-1 Vif-A3G axis is a valid target for developing small molecule-based new therapies for HIV infection or for enhancing innate immunity against viruses.}, address = {Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.}, author = {Nathans, Robin and Cao, Hong and Sharova, Natalia and Ali, Akbar and Sharkey, Mark and Stranska, Ruzena and Stevenson, Mario and Rana, Tariq M.}, citeulike-article-id = {3329302}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nbt.1496}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nbt.1496}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18806783}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18806783}, day = {21}, doi = {10.1038/nbt.1496}, issn = {1546-1696}, journal = {Nature biotechnology}, keywords = {treatment, vif}, month = {October}, number = {10}, pages = {1187--1192}, posted-at = {2008-09-29 22:04:58}, priority = {2}, title = {Small-molecule inhibition of HIV-1 Vif.}, url = {http://dx.doi.org/10.1038/nbt.1496}, volume = {26}, year = {2008} }

TY - JOUR ID - citeulike:3329302 L3 - citeulike-article-id:3329302 N2 - The HIV-1 protein Vif, essential for in vivo viral replication, targets the human DNA-editing enzyme, APOBEC3G (A3G), which inhibits replication of retroviruses and hepatitis B virus. As Vif has no known cellular homologs, it is an attractive, yet unrealized, target for antiviral intervention. Although zinc chelation inhibits Vif and enhances viral sensitivity to A3G, this effect is unrelated to the interaction of Vif with A3G. We identify a small molecule, RN-18, that antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degradation. RN-18 enhances Vif degradation only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome. These results demonstrate that the HIV-1 Vif-A3G axis is a valid target for developing small molecule-based new therapies for HIV infection or for enhancing innate immunity against viruses. IS - 10 JF - Nature biotechnology SN - 1546-1696 AD - Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. EP - 1192 TI - Small-molecule inhibition of HIV-1 Vif. VL - 26 SP - 1187 KW - treatment KW - vif AU - Nathans, Robin AU - Cao, Hong AU - Sharova, Natalia AU - Ali, Akbar AU - Sharkey, Mark AU - Stranska, Ruzena AU - Stevenson, Mario AU - Rana, Tariq PY - 2008/10/21/ UR - http://dx.doi.org/10.1038/nbt.1496 ER -