Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 andHIV-2 reverse transcriptases - Structural and biochemical analyses

Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-1 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolylthiourea (PETT) series of non-nucl eoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC50 of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC50 of 5 nM) and also in hibits HIV-2 RT (IC50 of 2.2 mu M). X-ray crystallographic structure determ inations of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compoun ds bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer b inding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT, PETT-2 was a noncompetitive inhibitor with respect to the dGTP su bstrate for both HIV-1 and HIV-2 RTs, PETT-2 was also a noncompetitive inhi bitor with respect to a poly(rC).(dG) template primer for HIV-2 RT. These r esults are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecti ng the binding of PETT-2 compared with PETT-1.