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

Ippolito JA, Niu H, Bertoletti N, Carter ZJ, Jin S, Spasov KA, Cisneros JA, Valhondo M, Cutrona KJ, Anderson KS, Jorgensen WL
ACS Med Chem Lett 12 249-255 (2021)
Related entries: 7krc, 7krd, 7kre

Cited: 9 times
EuropePMC logo PMID: 33603971

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.

Reviews citing this publication (3)

  1. Recent advances in the development of covalent inhibitors. Kim H, Hwang YS, Kim M, Park SB. RSC Med Chem 12 1037-1045 (2021)
  2. Sulfur(VI) fluorides as tools in biomolecular and medicinal chemistry. Carneiro SN, Khasnavis SR, Lee J, Butler TW, Majmudar JD, Am Ende CW, Ball ND. Org Biomol Chem 21 1356-1372 (2023)
  3. Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Vanangamudi M, Palaniappan S, Kathiravan MK, Namasivayam V. Viruses 15 1992 (2023)

Articles citing this publication (6)

  1. Sulfur fluoride exchange. Homer JA, Xu L, Kayambu N, Zheng Q, Choi EJ, Kim BM, Sharpless KB, Zuilhof H, Dong J, Moses JE. Nat Rev Methods Primers 3 58 (2023)
  2. Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase. Frey KM, Bertoletti N, Chan AH, Ippolito JA, Bollini M, Spasov KA, Jorgensen WL, Anderson KS. Front Mol Biosci 9 805187 (2022)
  3. Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study. Zhou Z, Meng B, An J, Zhao F, Sun Y, Zeng D, Wang W, Gao S, Xia Y, Dun C, De Clercq E, Pannecouque C, Zhan P, Kang D, Liu X. Int J Mol Sci 24 1215 (2023)
  4. Design, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase. Carter ZJ, Hollander K, Spasov KA, Anderson KS, Jorgensen WL. Bioorg Med Chem Lett 84 129216 (2023)
  5. Bioinspired Pyrano[2,3-<i>f</i>]chromen-8-ones: Ring C-Opened Analogues of Calanolide A: Synthesis and Anti-HIV-1 Evaluation. Khalymbadzha IA, Fatykhov RF, Butorin II, Sharapov AD, Potapova AP, Muthipeedika NJ, Zyryanov GV, Melekhin VV, Tokhtueva MD, Deev SL, Kukhanova MK, Mochulskaya NN, Tsurkan MV. Biomimetics (Basel) 9 44 (2024)
  6. Covalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase. Prucha GR, Henry S, Hollander K, Carter ZJ, Spasov KA, Jorgensen WL, Anderson KS. Eur J Med Chem 262 115894 (2023)


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