The non-nucleoside reverse transcriptase (RT) inhibitor RD4-2217 is a thiadiazole derivative that has proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. In this study we examined genotypic and phenotypic characteristics of RD4-2217-resistant mutants that have been obtained by serial passage of HIV-1 in MT-4 cells in the presence of increasing concentrations (0.05, 0.25, 1 and 10 μM) of the compound. The strains obtained, III(B/2217RE/0.05) and III(B/2217RE/0.25), were two- and 15-fold resistant to RD4-2217, respectively, whereas III(B/2217RE/1) and III(B2217RE/10) displayed 161- and > 238-fold resistance, respectively. Both III(B/2217RE/1) and III(B/2217RE/10) had two amino acid substitutions, V189I and T240I, in the RT. Furthermore, RD4-2217 did not inhibit the replication of an HIV-1 molecular clone, which had the same mutation, at concentrations up to 10 μM, indicating that the V189I plus T240I mutation confers high-level resistance to RD4-2217. Interestingly, the replicability of III(B/2217RE/1) and III(B/2217RE/10) appeared to be lower than that of wild-type III(B) in MT-4 cells, suggesting that the V189I plus T240I mutation may impair the enzymatic activity of HIV-1 RT.
ASJC Scopus subject areas
- Drug Discovery