Cryo-EM Structure of HIV-1 Reverse Transcriptase with N-Phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine: A New HIV-1 Non-nucleoside Inhibitor DOI
Megan A. Young, Thomas R. Lane, Renuka Raman

et al.

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

The use of highly active antiretroviral therapy (HAART) has made the human immunodeficiency virus (HIV) a chronic disease rather than terminal disease. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component HAART, although we seeing clinically relevant drug-resistant mutants such that there is need to develop new molecules. We recently identified class N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine HIV-1 NNRTI, with one known as compound 12126065, sub nanomolar (nM) potency in TZM-bl cells (HeLa expressing CD4, CCR5, and CXCR4) no vivo acute or subacute toxicity. now describe cryo-EM structure this molecule (resolution 3.53 Å) compare it analogues other NNRTIs. also synthesis activity five additional compounds, some which have promising against K103N/Y181C (A17) double mutant, will enable design future

Language: Английский

An Amazing 30-Year Journey around the DABO Family: A Medicinal Chemistry Lesson on a Versatile Class of Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors DOI Creative Commons
Emanuele Fabbrizi, Vladimir V. Chernyshov, Francesco Fiorentino

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Since the emergence of AIDS, non-nucleoside HIV-1 RT inhibitors (NNRTIs) have attracted attention scientists and clinicians due to their high potency specificity combined with low toxicity. 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) are a family NNRTIs described since 1992, best members among S-, NH-, N,N-DABOs showed anti-HIV-1 in both cellular enzymatic assays. During 30 years research, central 4-(3H)-pyrimidinone nucleus has been decorated 2,6-dihaloaryl or cyclohexyl groups at methylene C6, alkyl- (arylalkyl/aroylalkyl)thio/amino chains C2, hydrogen small alkyl group C5. The further introduction (i.e., methoxy) C6 α-benzylic position furnished sub-nanomolar level against wild-type nanomolar mutant strains. Importantly, some compounds DABO exhibited preventative microbicidal activity, valuable clinical settings where oral adherence rates low.

Language: Английский

Citations

0
Cryo-EM Structure of HIV-1 Reverse Transcriptase with N-Phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine: A New HIV-1 Non-nucleoside Inhibitor DOI
Megan A. Young, Thomas R. Lane, Renuka Raman

et al.

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

The use of highly active antiretroviral therapy (HAART) has made the human immunodeficiency virus (HIV) a chronic disease rather than terminal disease. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component HAART, although we seeing clinically relevant drug-resistant mutants such that there is need to develop new molecules. We recently identified class N-phenyl-1-(phenylsulfonyl)-1H-1,2,4-triazol-3-amine HIV-1 NNRTI, with one known as compound 12126065, sub nanomolar (nM) potency in TZM-bl cells (HeLa expressing CD4, CCR5, and CXCR4) no vivo acute or subacute toxicity. now describe cryo-EM structure this molecule (resolution 3.53 Å) compare it analogues other NNRTIs. also synthesis activity five additional compounds, some which have promising against K103N/Y181C (A17) double mutant, will enable design future

Language: Английский

Citations

0