Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography

Significance HIV-1 reverse transcriptase (RT) has been the prime target for anti-HIV chemotherapy; however, its rapid mutation often generates drug resistance. Prominent variant strains of HIV-1 that lead to treatment failure with nonnucleoside RT inhibitors (NNRTIs) bear the Tyr181Cys mutation in RT. Based on our previous discovery and crystallography for potent noncovalent NNRTIs, new compounds were designed with incorporation of chemical warheads intended to modify covalently Cys181. Here we report on the success of the strategy, including biochemical, biophysical, and cellular evidence of the desired irreversible covalent inhibition. The new compounds completely eliminate the activity of Cys181-bearing RT, and it may be possible to dose them less frequently than noncovalent inhibitors.