2. Academic Validation
  3. Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead

Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead

  • ACS Med Chem Lett. 2021 Jan 6;12(2):249-255. doi: 10.1021/acsmedchemlett.0c00612.
Joseph A Ippolito 1 2,  Haichan Niu 1,  Nicole Bertoletti 2,  Zachary J Carter 1,  Shengyan Jin 2,  Krasimir A Spasov 2,  José A Cisneros 1,  Margarita Valhondo 1,  Kara J Cutrona 1,  Karen S Anderson 2 3,  William L Jorgensen 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
  • 2 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
  • 3 Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States.
PMID: 33603971 DOI: 10.1021/acsmedchemlett.0c00612
Abstract

Covalent inhibitors of wild-type HIV-1 Reverse Transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the Enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC50 values for in vitro inhibition of WT RT and EC50 values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.

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