New Entities (NE Program)

Scientific Papers

HIV Integrase Inhibitor

Rationale:

• New viral target to treat HIV/AIDS

Targeted Indications:

• Treatment of HIV/AIDS
• Resistant strains

Development Stage:

• Phase 1 trial expected to initiate in 2007/2008

Many of the antiviral drugs used today in HIV therapy are first generation drugs: efficient but with a risk of limited efficacy, debilitating side effects, and inadequate formulation. The main concern, however, is that some 50 - 75% of HIV patients on drug therapy experience drug or multi-drug resistance. In addition 20% of newly diagnosed patients are now presenting drug resistance.

Computational docking onto the catalytic core domain confirmed the drug pharmacophore and pointed to a preferential binding site from which guidelines were derived for the improvement of new inhibitors.

The integrase field represents a novel target for the treatment of AIDS. Integration of the viral genome is an essential step in the retrovirus life cycle. The interest in structural studies of retroviral integrase has been largely driven by urgent need to develop a new class of AIDS drug due to resistance issues. HIV integrase has been a preferred subject as the enzyme was expected to provide a potential target for selecting and or designing compounds that would have different clinical properties than existing drugs that inhibit reverse transcriptase and protease.

BioAlliance has built a solid expertise on integrase through academic alliances and contracts with experts, including Jean-François Mouscadet, Director of Research at the Laboratory for Biotechnology and Applied Pharmacology, l’Ecole Normale Supérieure de Cachan, France, and international expert on integrase.

An ex vivo screening tool has been developed, allowing the assessment of cellular antiviral activity and the identification of the precise mechanism of action. The resistance activity profile (induction of resistant strains or activity against multi-resistant strains) was particularly studied.

Styrylquinolines: A New Chemical Class

A large panel has been tested with chemical compounds from private chemical libraries. The screening resulted in the validation of the anti-integrase activity of a family of compounds: the Styrylquinoline derivatives. This family is fully patented and BioAlliance holds worldwide rights.

Finally a lead candidate based on a large therapeutic index has been selected for development (FZ 41). Regarding the cellular activity, FZ 41 is capable of suppressing the viral replication at non-toxic concentrations and is active also against resistant strains. FZ 41 is a compound acting on integrase and is efficient on multi-resistant strains (Reverse transcriptase or other integrase inhibitors). The next development stages include scaling up, analytical, bioavailablility and toxicological studies before starting human Phase I clinical trials expected to begin in 2006.

Scientific Papers