16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

PL-100, A NOVEL PROTEASE INHIBITOR WITH A HIGH GENETIC BARRIER

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0304

Dandache S.¹, Wainberg M.A.², Panchal C.¹, Wu J.J.^1
1 Ambrilia Biopharma Inc., Verdun, Canada, ² McGill University, Montreal, Canada

BACKGROUND: The development of new HIV inhibitors with distinct resistance profiles is paramount to derailing the emergence of multi-resistant strains. Our drug discovery program integrated viral resistance into the screening process and produced PL-100, a novel potent Protease Inhibitor (PI). A 48-week in vitro resistance selection study was performed to see how readily HIV developed resistance to PL-100.

RESULTS: Mononuclear cells infected with a laboratory-adapted strain were subjected to increasing concentrations of PL-100. We observed a marked delay in the emergence of a virus growing in presence of PL-100 compared to amprenavir. Four mutations in the Protease were selected after 25 weeks: two flap mutations (K45R and M46I) and two novel active site mutations (T80I and P81S). Site-directed mutagenesis revealed that all four mutations were required to develop a relatively mild resistance to PL-100. Importantly, these mutations did not cause cross-resistance to currently marketed PIs. On the contrary, one of the mutations was even shown to cause hypersensitivity to a few PIs. Western blot analysis of p55Gag processing showed that a defect in Protease activity caused by one mutation could only be compensated when the other mutations were present. These data correlated well with the replication capacity (RC) of the mutant viruses as measured by a standard viral growth assay, since only the quadruple mutant's RC approached that of the wild type.

CONCLUSIONS: PL-100 is a promising new PI that forces HIV into a unique mutational pathway that conferred only a mild resistance to our drug and that proved detrimental to its replication capacity. No cross-resistance to other PIs was observed. The mutational pathway made the virus more sensitive to a few other PIs that could potentially be applied in combination with PPL-100, a phosphorylated form of PL-100 currently in Clinical Phase I trials in Canada, in a more potent HAART regime.

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2006-08-13
ThAa0304

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