In this report period, we carried on our long-standing research line, development of anti-HIV drugs, however, we particularly focused our effort to develop antiretroviral agents which resist the emergence of drug-resistant HIV-1 variants, in response to the rapidly growing problem, drug failure in patients with HIV-1 infection. We also made efforts to enhance/improve antiviral efficacy in patients by physiologically altering cellular metabolisms. Over the past four years, we designed and synthesized ~300 potential HIV protease inhibitors in collaborations with intra- and extramural investigators and identified JE-2147, a novel allophenylnorstatine (apns)-containing dipeptide HIV protease inhibitor (PI) potent against a wide spectrum of HIV-1, HIV-2, SIV, and clinical HIV-1 strains, and in particular, against multi-PI-resistant HIV-1 strains with IC50 values ranging from 13-41 nM in vitro. Our structural analysis revealed that the presence of a flexible P2i moiety is important for the potency of JE-2147 toward wild type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs which resist the emergence of PI-resistant HIV-1 (Proc. Natl. Acad. Sci. USA, 96: 8675-80, 1999). It is of note that JE 2147 is currently undergoing preclinical and clinical development in the US. Most recently, we have identified another novel protease inhibitor, UIC-003, in collaboration with scientists in University of Chicago and NCI-FCRDC. This novel compound is extremely potent against HIV-1 with IC50 values of less than nanomolar concentrations (~0.5 nM). UIC-003 is also potent against multi-PI-resistant clinical strains at nanomolar concentrations (ranging from 1-6 nM). An HIV-1 population, which was propagated in vitro in the presence of increasing concentrations of UIC 003 and became less susceptible to the compound, still had IC50 values of 0.01 microM, which appear to be relatively easily maintained in vivo. Such HIV-1 mutants had a unique mutation at codon 28 of the protease-encoded gene, indicating that this novel compound binds to a unique site (or subsites) of the target protease. In 1993, we identified a set of novel mutations [Ala-62
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