[NATAP] PL-100, New Protease Inhibitor

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PL-100, New Protease Inhibitor

Reported by Jules Levin

14th Intl HIV Drug Resistance Workshop

June 7-11, 2005

Quebec City, Canada

“PL-100 and its derivatives, a novel class of potent human immunodeficiency virus type 1 protease inhibitors: resistance profile and pharmacokineticsâ€

JJ Wu1, G Sévigny1, BR Stranix1, S Dandache1, M Petrella1, M Ge1, G Milot1, J Yelle1, C Panchal1, N Parkin2, JM Schapiro3 and MA Wainberg4

1Procyon Biopharma Inc, Montreal, Canada

2ViroLogic Inc, South San Francisco, CA, USA

3National Hemophilia Centre, Israel; 4McGill University, Montreal,

Canada

BACKGROUND: We previously reported PL-100 as a potent, specific and non-cytotoxic HIV-1 protease inhibitor (PI). A small study was initially conducted to probe the cross-resistance profile of PL-100 against 14 multi-PI-resistant HIV isolates. Here, we have further characterized cross-resistance profiles of PL-100 and its derivative, PL-337 against 49 additional HIV isolates with reduced susceptibility to approved PIs. We also studied emergence of mutations conferring resistance to PL-100 in vitro. Furthermore, we developed a

phosphorylated pro-drug, PPL-100 from PL-100 to improve its pharmacokinetic profile.

METHODS: Cross-resistance profiles of PL-100 and PL-337 were established using PhenoSenseTM assay (ViroLogic Inc). For comparison, atazanavir, saquinavir, indinavir, nelfinavir, amprenavir and lopinavir were tested in parallel. For selection of resistance mutations to PL-100, we used blood mononuclear

cells with a standard procedure of progressive increments of PI concentrations. Viral kinetics and genotyping were analysed by established methods. Water solubility of PPL-100 was determined by HPLC/UV and LC/MS methods and pharmacokinetic profile of PPL-100 was evaluated in rats.

RESULTS: In cross-resistance profiling against 63 diverse PI-resistant viruses, PL-100 and PL-337 had a median EC50 fold-change (FC) of 3.6 and 4.6, respectively. The median EC50 FC of the six approved PIs ranged from 8.1 (indinavir) to 23 (saquinavir). The percentage of resistant strains with EC50 FC <10 to PL-100 and PL-337 were 76 and 72, respectively. In comparison, the percentage of strains with FC<10 to approved drugs ranged from 27 (nelfinavir) to 54 (indinavir). PL-100 and PL-337 shared a very similar cross-resistance pattern, distinct from approved PIs.

After 25 weeks of passaging under PL-100 selective pressure, preliminary data revealed a novel pattern of mutations (K45R, M46I, T80I, and P81S), some of them potentially polymorphic, in the PR gene of laboratory-adapted strain IIIB. The impact of these mutations on PL-100 antiviral activity is currently under

investigation. PPL-100 was >1000-fold more water soluble than PL-100 and showed two to threefold improvement over PL-100 in oral bioavailability and other parameters.

CONCLUSIONS: The combination of a favourable cross-resistance profile, and improved solubility and pharmacokinetics confirms the potential of PPL-100 as a novel PI for treatment of patients infected with PI resistant HIV-1 strains.