“…Currently, six structurally distinct NNRTIs were approved by FDA for clinical HIV treatment, but the rapid emergence of resistant strains inevitably reduced the effectiveness of existing drugs. The single mutants are mainly composed of L100I, K101E, E138K, K101P, P225H, M230L, K238T, F227L, V106A/M, K103N/S, Y188L/C/H, Y181C/I/V, and G190A/S/E and the double mutants mainly consist of K103N + L100I and K103N + Y181C. − New data on HIV drug resistance from Stanford University in 2022 reveal that first-generation inhibitors are partially or completely insensitive to drug-resistant strains, such as Y181C, P236L, and K103N, whereas second-generation NNRTIs were significantly less susceptible to mutant strains such as K101E, E138K, and Y181V . As two well-known FDA-approved second-generation NNRTIs, etravirine (ETR, 1 ) and rilpivirine (RPV, 2 ), structurally characterized by a typical diarylpyrimidine (DAPY) moiety, possessed excellent broad-spectrum antiviral activity toward wild-type (WT) HIV-1 and several clinically mutant strains .…”