JE-2147: A dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1

We designed, synthesized, and identified JE-2147, an allophenylnorstatine-c ontaining dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various c linical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isol ated from seven patients who had failed 9-11 different anti-HIV therapeutic s after 32-83 months, had a variety of drug-resistance-related amino acid s ubstitutions and were highly and invariably resistant to all of the current ly available anti-HIV agents. JE-2147 was, however, extremely potent agains t all such drug-resistant strains, with IC50 values ranging from 13-41 nM ( <2-fold changes in IC50 compared with that of wild-type HIV-1). The emergen ce of JE-2147-resistant HIV-1 variants in vitro was substantially delayed c ompared with that of HIV-1 resistant to another allophenylnorstatine-contai ning compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the u se of flexible components may open a new avenue for designing PIs that resi st the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.