r&d

FlecheHIV

HIV infection, AIDS pandemic and antiretroviral resistance

The AIDS pandemic is a major public health problem. In fact, the number of people living with HIV is estimated at around 33.2 million, mostly in sub-Saharan Africa.

Tri-therapy

With the introduction of the tri-therapy – a combination therapy of at least three drugs with different mechanisms of action – the HIV infection has become a chronic disease that requires lifelong treatment. The incidence of HIV infection has stabilized globally and began to decline in many countries. The number of people with antiretroviral therapy continues to increase and recent clinical trials have confirmed the positive impact of antiretroviral therapy on the controlling of the AIDS pandemic and HIV prevention.

Drug resistance

However, despite these advances, too many people still get infected and the emergence and spread of viruses resistant to drugs available on the market remains a major problem. Drug resistance is a growing concern due to:

•  The dramatic increase in life expectancy of people with HIV that approaches that of healthy individuals, while still not reaching it.

 The tendency to start treatment at a more and more early stage in the development of the disease, at an increasingly high CD4 rate.

•  Lack of compliance to treatment due to side effects in the long term.

Current researches

In the United States and Europe, recent studies show that the risk of being infected with a virus resistant to at least one antiretroviral class is 6 to 16%.That of being infected by a virus resistant to more than one class is 3 to 5%. New antiretroviral drugs, with new mechanisms of action and active on currently resistant viruses, are therefore essential.

RetD bandeau

MUTABILIS targets virus-host interaction and develops a new generation of antiretroviral drugs

New antiretroviral generation

To address this problem, MUTABILIS is developing a new generation of original and innovative antiretrovirals drugs, based on a new mode of therapeutic action. Instead of targeting the catalytic activity of viral enzymes, like most drugs, MUTABILIS targets virus-host interaction that is essential for viral replication. Drugs operating through this new mode of action offer key advantages: complementarity with all other existing drugs and a lack of sensitivity to cross-resistance mechanisms.

Host-virus interaction

The host-virus interaction is an emerging field in the pathogenesis of viral diseases. The scientific Director at MUTABILIS, R. Benarous, has contributed to the discovery of LEDGF as a cellular co-factor of HIV integrase essential in the integration and full replication of the virus. LEDGF, by binding to integrase, allows the integration of HIV in the transcriptionally active regions of chromatin. Early 2010, the MUTABILIS program began with the searching for drugs targeting the interaction between integrase and LEDGF. This program led to the discovery of new powerful and promising antiviral agents, one of them is currently in pre-clinical phase.

Mutabilis drug candidate

This drug candidate and its backups are original allosteric inhibitors of integrase-LEDGF interaction (INLAIs) that were co-crystallized with the catalytic domain of the integrase in the LEDGF binding site. They present a potent antiretroviral activity in the nanomolar range, are active against all tested HIV-1 isolates, including isolates from various clades, and kept their full activity against resistant viruses to current drugs. MUTABILIS Researchers (Le Rouzic et al. 2012)¹ and other teams² have recently shown that these INLAIs have a dual mode of action: first they inhibit viral integration and then they disturb, in the post-integration phase, the production of infectious viral particles. The antiretroviral activity of INLAIs at post-integration stage is by far the most important. This dual mode of action of INLAIs acting at two different stages of the replication cycle of HIV, is unique and unprecedented with other classes of antiretroviral agents. This could give a significant advantage to this new family of compounds from a therapeutic point of view. The lack of antagonism between INLAIs and INSTIs and other families of drugs currently on the market is an asset that enhances their potential as future antiretroviral drug.

Microscope
¹Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Le Rouzic E, Bonnard D, Chasset S, Bruneau JM, Chevreuil F, Le Strat F, Nguyen J, Beauvoir R, Amadori C, Brias J, Vomscheid S, Eiler S, Lévy N, Delelis O, Deprez E, Saïb A, Zamborlini A, Emiliani S, Ruff M, Ledoussal B, Moreau F, Benarous R. Retrovirology. 2013 Nov 21;10:144. doi: 10.1186/1742-4690-10-144.
²Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Jurado KA, Wang H, Slaughter A, Feng L, Kessl JJ, Koh Y, Wang W, Ballandras-Colas A, Patel PA, Fuchs JR, Kvaratskhelia M, Engelman A. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8690-5. doi: 10.1073/pnas.1300703110. Epub 2013 Apr 22.