[20] ANTIVIRAL ACTIVITY OF P-1946, A NOVEL ANTI-HIV PROTEASE INHIBITOR

12th International HIV Drug Resistance Workshop

10–14 June 2003, Cabo del Sol, Los Cabos, Mexico

ANTIVIRAL ACTIVITY OF P-1946, A NOVEL ANTI-HIV PROTEASE INHIBITOR

Antivir Ther. 2003; 8:S23 (abstract no. 20)

G Sévigny¹, B Tian¹, A Dubois¹, B Stranix¹, G Sauvé⁴, C Petropoulos², Y Lie², N Hellmann², B Conway³ and J Yelle¹
¹Pharmacor, Inc., Laval, Canada; ²ViroLogic, Inc., South San Francisco, Calif., USA; ³UBC, Department of Pharmacology & Therapeutics, Vancouver, Canada; and ⁴INRS-Institut Armand- Frappier, Laval, Canada

BACKGROUND: The use of protease inhibitors (PIs) in the treatment of HIV infection has led to significant improvement in AIDS-related morbidity and mortality. Unfortunately, the rapid emergence of HIV strains resistant to currently available antiretroviral drugs threatens to make obsolete the current therapeutic approaches. Therefore, novel PIs with distinct resistance profiles are needed to help resolve this dilemma.

METHODS: PIs derived from an amino acid were prepared using a simple, straightforward synthesis scheme developed in our laboratory. Antiviral activity (EC₅₀) of the candidate compounds was determined for wild-type and mutant viral strains, using MT-4 as the cell line. The assay was based on the inhibition of HIV-induced cytopathic effect, measuring cell viability by MTT colorimetric assay. The threshold for phenotypic resistance to the test compound was defined as fold resistance (EC_50test/EC_50wt)>4.0.

RESULTS: A novel family of amino acid derivatives was readily obtained in few synthetic steps using classic chemistry. The five compounds (P-1933, P-1935, P-1939, P-1946, P-1999) with the highest antiviral activity against the wild-type HIV-1 NL4.3 virus (EC₅₀<400 nM) also remained active against two typical strains carrying mutations 48/90 (saquinavir-resistant strain) and 10/46/63/82/84 (strain 4596). Compound P-1946 was selected as a prototype of the family and further characterized. P-1946 displayed good antiviral activity against wild-type strain NL4.3 (EC₅₀=150 nM). Cytotoxicity (CCIC₅₀) of P-1946 was 40 µM, in the same range as currently marketed PIs. In order to define the resistance profile of P-1946, we analysed the antiviral activity in the presence of protease mutations at amino acids 10, 46, 48, 63, 82, 84 and 90, using HIV strains obtained from the NIH. In addition to saquinavir-resistant and 4596 strains, P-1946 was active (fold resistance <4) in the presence of combined mutations 82/84, which are associated with resistance to several PIs, including cyclic urea. Eight additional viruses were used to better define the phenotypic resistance profile of P-1946 using the PhenoSense assay (ViroLogic, Inc.). The compound remained fully active in the presence of mutation at position 30 or 50, which are associated with resistance to nelfinavir and amprenavir, respectively. Significant resistance to P-1946 required the presence of at least six mutations in the protease gene.

CONCLUSIONS: P-1946 is an amino acid derivative typical of a new family of PIs. Its antiviral activity profile makes it a good lead compound for the development of new potent agents that would offer therapeutic alternatives for individuals carrying isolates resistant to current PIs.

PRESENTING AUTHOR: G Sévigny

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2003-07-08
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