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Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants

Smith, SJ and Pauly, GT and Akram, A and Melody, K and Rai, G and Maloney, DJ and Ambrose, Z and Thomas, CJ and Schneider, JT and Hughes, SH (2016) Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants. Retrovirology, 13 (1).

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Background: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs. Results: Using a single-round infection assay, we identified several RPV analogs that potently inhibited a broad panel of NNRTI resistant mutants. Additionally, we determined that several resistant mutants selected by either RPV or Doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogs. Conclusions: The antiviral data suggested that there are RPV analogs that could be candidates for further development as NNRTIs, and one of the most promising compounds was modeled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Smith, SJ
Pauly, GT
Akram, A
Melody, Kkpm20@pitt.eduKPM20
Rai, G
Maloney, DJ
Ambrose, Zzaa4@pitt.eduZAA4
Thomas, CJ
Schneider, JT
Hughes, SH
Date: 16 February 2016
Date Type: Publication
Journal or Publication Title: Retrovirology
Volume: 13
Number: 1
DOI or Unique Handle: 10.1186/s12977-016-0244-2
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
School of Medicine > Infectious Diseases and Microbiology
School of Medicine > Medicine
Refereed: Yes
Date Deposited: 22 Aug 2016 17:41
Last Modified: 30 Mar 2021 13:56


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