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

Abstract

Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether nonnucleoside 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 IC 50 values for in vitro inhibition of WT RT and EC 50 values for cytopathic protection of HIV-1-infected human T-cells in the 5−320 nM range.

Recent advances in the development of covalent inhibitors

“…Thus, they can be used to target largely non-overlapping groups of human proteins such as neutrophil elastase 31 and HIV-1 reverse transcriptase. 32 In 2020, Kelly et al further demonstrated that sulfuramidimidoyl fluorides, a class of weak electrophiles, undergo SuFEx chemistry by applying the IDD approach (Fig. 6a).…”

Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase

“…Extensive SAR has been conducted to design novel NNRTIs with improved resistance profiles and optimal physiochemical properties ( Bollini et al, 2011 ; Jorgensen et al, 2011 ; Lee et al, 2013 ; Lee et al, 2014 ; Lee et al, 2015 ; Chan et al, 2017 ; Ippolito et al, 2021 ). Through each iteration of design, new insights were gained regarding key interactions with RT and the NNIBP.…”

Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

“…Therefore, based on the cocrystal structures of 8 and WT RT (Figure ), a series of fluorosulfate-bearing derivatives of compound 8 were designed in light of the stability of fluorosulfate and its relatively modest electrophilicity (Figure ). As a result, compounds 45 – 47 were identified as covalent inhibitors by the crystallographic studies . As shown in Figure , these compounds covalently modified Tyr181 to form biaryl sulfate between tyrosine and the fluorosulfate group.…”

“…As a result, compounds 45−47 were identified as covalent inhibitors by the crystallographic studies. 123 As shown in Figure 22, these compounds covalently modified Tyr181 to form biaryl sulfate between tyrosine and the fluorosulfate group. Generally, the inhibitory potency of covalent inhibitors improves with the extension of the incubation time, and non-covalent inhibitors are not affected.…”