HIV-1 RT is a key enzyme responsible for viral replication and subsequent perpetuation of viral infection. Hence, it has been the primary target for therapeutic intervention against HIV-1 infection. However, rapid emergence of drug-resistant viral strains harboring enzymatically-active mutant RT with reduced drug-sensitivity has frustrated all efforts to control the spread of HIV-1 infection. The mechanism of resistance to nucleoside inhibitors seems to be quite complex since a number of mutational sites do not cluster around the putative dNTP-binding pocket in the polymerase cleft. However, for nonnucleoside RT inhibitors (NNRTIs), a common hydrophobic binding region is seen in the crystal structures of RT liganded with these inhibitors. The side chains of a number of hydrophobic residues located in the fingers, palm and thumb subdomains in the p66 subunit converge to form a hydrophobic NNRTI binding pocket. Any mutational change in these hydrophobic residues reduces the drug-sensitivity due to alteration in the NNRTI-binding pocket. Our proposal seeks to address this problem by developing a group of new NNRTIs which are effective against both the wild type and common drug-resistant variants of HIV-1 RT. Using a combination of structure-based molecular modeling and in vitro assays, we have selected four distinct lead compounds from a large repertoire of compounds displaying inhibitory activity against both wild type and mutant RT. We plan to further modify these lead compounds by a structure-based design strategy to improve their inhibitory potential followed by synthesis and in vitro anti-HIV-1 RT screening. PUBLIC HELATH
The major focus of this proposal is to develop a new class of NNRTIs that is equally effective against both the wild type and drug-resistant variants of HIV-1 RT. We selected four nonnucleoside lead compounds from a large repertoire of compounds based on structure-based modeling and in vitro anti- RT activity against both the wild type HIV-1 RT and drug-resistant RT mutants. These initial lead compounds will be modified to further enhance their anti-RT activity.
| Pandey, Nootan; Mishra, Chaturbhuj A; Manvar, Dinesh et al. (2011) The glutamine side chain at position 91 on the ?5a-?5b loop of human immunodeficiency virus type 1 reverse transcriptase is required for stabilizing the dNTP binding pocket. Biochemistry 50:8067-77 |
| Upadhyay, Alok K; Talele, Tanaji T; Pandey, Virendra N (2010) Impact of template overhang-binding region of HIV-1 RT on the binding and orientation of the duplex region of the template-primer. Mol Cell Biochem 338:19-33 |
| Upadhyay, Alok; Pandey, Nootan; Mishra, Chaturbhuj A et al. (2010) A single deletion at position 134, 135, or 136 in the beta 7-beta 8 loop of the p51 subunit of HIV-1 RT disrupts the formation of heterodimeric enzyme. J Cell Biochem 109:598-605 |
| Talele, Tanaji T; Upadhyay, Alok; Pandey, Virendra N (2009) Influence of the RNase H domain of retroviral reverse transcriptases on the metal specificity and substrate selection of their polymerase domains. Virol J 6:159 |
