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Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 gag-pol

Figueiredo, Anna, Moore, Katie L., Mak, Johnson, Sluis-Cremer, Nicolas, de Bethune, Marie-Pierre and Tachedjian, Gilda 2006, Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 gag-pol, PLoS pathogens, vol. 2, no. 11, pp. 1051-1059, doi: 10.1371/journal.ppat.0020119.

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Title Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 gag-pol
Author(s) Figueiredo, Anna
Moore, Katie L.
Mak, JohnsonORCID iD for Mak, Johnson orcid.org/0000-0002-5229-5707
Sluis-Cremer, Nicolas
de Bethune, Marie-Pierre
Tachedjian, Gilda
Journal name PLoS pathogens
Volume number 2
Issue number 11
Start page 1051
End page 1059
Total pages 9
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2006-11
ISSN 1553-7366
1553-7374
Keyword(s) amino acid sequence
dimerization
dose response
drug mechanism
enzyme activation
HeLa cell
human cell
Human immunodeficiency virus 1
in vitro study
myristylation
nucleotide sequence
protein processing
two hybrid system
virion
virus inhibition
virus particle
virus replication
Summary 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.
Language eng
DOI 10.1371/journal.ppat.0020119
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2006, Public Library of Science
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047593

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.