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New HIV Protease Inhibitor PL-100
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"....Single, double, or triple viral mutants did not show resistance to PL-100.... only mild resistance to PL-100 was observed with the quadruple viral mutant.... data suggest that PPL-100 is likely a QD PI without RTV boosting...."
Reported by Jules Levin
15th Intl Resistance Workshop, June 13-17, Sitges, Spain
"The HIV-1 protease inhibitor PL-100 has a high genetic barrier and selects a novel pattern of mutations"
JJ Wu1, S Danache1, B Stranx,1, C Panchal1, and MA Wainberg2
1Ambrilia Biopharma Inc, 2McGill University, Montreal, Canada
BACKGROUND: PL-100 is a novel HIV-1 protease inhibitor (PI) with a favourable cross-resistance profile. Its phosphorylated pro-drug PPL-100, with significantly improved solubility and pharmacokinetics, has potential as a QD PI and is currently in Phase I human clinical trials.
METHODS: Mononuclear cells infected with laboratory-adapted HIV-1 strain IIIB were subjected to increasing concentrations of PL-100 or amprenavir. Sequencing of the protease (PR) region of viruses was performed using Bayer's HIV genotyping test. Quickchange site-directed mutagenesis kit was used to introduce identified PR mutations into pNL-4.3. Phenotyping of produced viral mutants was performed using MT-4 cytoprotection assay (MTT). Standard viral growth studies were conducted in MT-4 cells to analyze viral replication capacity.
RESULTS
While amprenavir selected for the expected signature mutations, after 48 weeks of passaging under increasing selective pressure of PL-100, a novel pattern was observed of mutations (K45R, M46I, T80I, and P81S) in the PR gene. T80I was observed at week 8. All other mutations did not appear until week 25. No further mutations were observed up to 48 weeks. K45R and M46I are known mutations in the flap region; T80I and P81S are novel mutations in the active site. Site-directed mutagenesis reveals that P81S is a lethal mutation, since the replication capacity of various mutants containing this mutation was severely impaired except the mutant containing all four mutations (K45R, M46I, T80I, P81S). These observations correlated well with loss of PR activity in the P81S mutants and recovery of proteolytic activity when all four mutations present, as measured by p55 Gag processing.
Single, double, or triple viral mutants did not show resistance to PL-100 (EC50 fold-change [FC] <2.5), while only mild resistance to PL-100 was observed with the quadruple viral mutant (FC=10.8). No cross-resistance to amprenavir, lopinavir, atazanavir, saquinavir, indinavir, and nelfinavir was observed (FC<2.5) for any viral mutants. Interestingly, T80I induced hypersensitivity (22-fold) to saquinavir. Finally, pharmackinetic data suggest that PPL-100 is likely a QD PI without RTV boosting.
CONCLUSION: The novel mutational pathway and favourable pharmacokinetic profile justify further clinical development of the drug to treat PI-naïve and experienced patients.
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