ABSTRACT:
We have identified and characterized a potent new non-nucleoside reverse transcriptase (RT) inhibitor HIV-1 that also is inhibitory against HIV-2. SJ-3366 inhibits HIV-1 replication at concentrations below 1 nM with a therapeutic index of greater than 4,000,000. SJ-3366 inhibited HIV-2 at a concentration of approximately 2.7-3.8 nM in replicate assays with a mixed mechanism of inhibition (both the Km and Vmax were affected by the compound). In these enzymatic assays, SJ-3366 was specific for HIV-1 and did not inhibit HIV-2 RT. Typical of most NNRTIs, the compound lost activity when challenged with HIV-1 strains possessing Y181C, K103N and Y188C amino acid changes in the RT. Combination anti-HIV assays indicated an additive interaction with all rested compounds with the exception of didanosine, where a synergistic interaction was observed. No antagonism or synergistic toxicity was observed. We have selected for a resistant strain that is completely insensitive to SJ-3366. This resistant strain has been characterized for mutations conferring resistance to both virus attachment and RT inhibition. Other resistance engendering mutation may confer increased fitness or compensate for fitness-decreasing amino acid changes. Based on its significantly elevated therapeutic index and multiple mechanisms of anti-HIV action, SJ-3366 represents an exciting new compound for use in HIV-infected individuals.
