3rd International Workshop on HIV Drug Resistance & Treatment Strategies


23-26 June 1999, San Diego, California, USA

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KINETIC CHARACTERIZATION OF RS-344, AN HIV-1 PROTEASE INHIBITOR DESIGNED WITH A 'RESISTANT REPELLENT' CORE

Antiviral Therapy 1999;4 (Suppl 1):5 (abstract no. 6)

L Suvorov, S Gulnik, E Gustchina, B Yu, R Randad, M Eissenstat and J Erickson
SAIC Frederick, NCI-FCRDC, Frederick, Maryland, USA

Despite the current success in HIV treatment with protease inhibitors, the emergence of resistant virus strains limits effectiveness of such compounds. The acquisition of mutations in HIV protease, especially in the active site regions, resulted in a high degree of cross-resistance towards many different protease inhibitors, including all clinically approved drugs. Using structure-based approaches a novel flexible core was designed to target some of the active site mutants. Using a continuous fluorogenic assay, we measured the inhibition constants for one such inhibitor, RS-344, towards wild-type and seven different drug-resistant mutant enzymes. Inhibition constants were compared with those obtained for saquinavir, indinavir, ritonavir, nelfinavir, amprenavir and ABT378 (RS346). Compared to clinically approved drugs, RS-344 exhibited similar potency in both enzymatic and cell culture assays (Ki~10 pm, IC50=23 nM). Our study shows that several HIV protease mutants containing the V82A (V82A, M46F/V82A, G48V/V82A) substitution, which usually show cross-resistance to many inhibitors in biochemical assays, remained sensitive to RS-344. For example double mutant G48V/V82A exhibits 15-50-fold increase of Ki towards saquinavir, indinavir, ritonavir and nelfinavir, but was much more sensitive to RS-344 (<4-fold increase of Ki). Significantly lower Ki changes were also observed for RS-344 in comparison to clinically approved inhibitors towards other active site mutants including I84V, V82F/I84V and G48V/L90M. Overall, the biochemical resistance profile of RS-344 supports our idea that core flexibility is important in the design of resistance repellent inhibitors for HIV-1 protease.

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