mak-potentnonnucleoside-2006.pdf (929.32 kB)
Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 gag-pol
journal contributionposted on 2006-11-01, 00:00 authored by A Figueiredo, K Moore, Johnson Mak, N Sluis-Cremer, M P de Bethune, G Tachedjian
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) target HIV-1 reverse transcriptase (RT) by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA. NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions. However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood. Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication. These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells. The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence. These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production. Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation.
Pagination1051 - 1059
PublisherPublic Library of Science
LocationSan Francisco, Calif.
Publication classificationC1.1 Refereed article in a scholarly journal
Copyright notice2006, Public Library of Science
amino acid sequencedimerizationdose responsedrug mechanismenzyme activationHeLa cellhuman cellHuman immunodeficiency virus 1in vitro studymyristylationnucleotide sequenceprotein processingtwo hybrid systemvirionvirus inhibitionvirus particlevirus replicationScience & TechnologyLife Sciences & BiomedicineMicrobiologyParasitologyVirologyPOLYPROTEIN PRECURSORIMMUNODEFICIENCYPROTEASEMECHANISMEFAVIRENZMUTATIONSDIMERPR160(GAG-POL)REPLICATIONMicrobiologyImmunology