Maturation and assembly inhibitors

After new viral enzymes, proteins, and genetic material are produced and processed, they must be packaged together into new viral particles. These components are first enclosed in a capsid, which is then surrounded by an envelope as it ‘buds’ out of the cell to become a complete virion. As with the other steps of the HIV life-cycle, viral assembly and maturation offer several potential targets for new therapies.

Bevirimat (formerly PA-457) is a betulinic acid derivative that interferes with the production of the HIV capsid by preventing cleavage of the precursor Gag protein. The drug has had a troubled history with formulation and bioavailability issues, as well as questionable efficacy in treatment-experienced individuals who have developed gag polymorphisms.

Myriad Genetics bought bevirimat, now called MPC-4326, from Panacos in 2009. Later in the year, results from Study 204, a phase II dose-ranging clinical trial were presented. While not showing impressive antiviral activity, a genotypic test has been developed to predict those most likely to respond to the drug. A larger phase IIb study of bevirimat, formulated as a 100mg tablet, was planned, but in 2010 Myriad announced that it was halting further development to concentrate on other products, and seeking a development partner to take the drug further.1 2 

The same company is also starting a dose-ranging phase IIA clinical trial of its other maturation inhibitor, Vivecon (MPC-9055). Results from a phase I study in HIV-negative participants found the drug to be safe, with good bioavailability. Laboratory tests indicate it may be effective against virus resistant to drugs in the non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor classes.

Panacos has moved on to development of a ‘second generation’ maturation inhibitor, PA-1050040, which appears to have better bioavailability and the ability to overcome gag polymorphism. They have also begun work on a third-generation drug that is chemically distinct from bevirimat.3 

Another maturation inhibitor, UK-201844, is also in early development. It is intended to interfere with gp160 processing, resulting in virions with non-functional Env proteins.4

References

  1. Bloch M et al. Efficacy, safety and pharmacokinetics of MPC-4326 (bevirimat dimeglumine) 200mg BID and 300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-1230, 2009
  2. Lalezari J et al. Pharmacokinetics and safety of a novel 100 mg tablet formulation of MPC-4326 in subjects with HIV-1 infection. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract A1-1309, 2009
  3. Kilgore N et al. Characterization of PA1050040, a second generation HIV-1 maturation inhibitor. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, abstract MOPDX05, 2007
  4. Wade SB et al. Identification and characterization of UK-201844, a novel inhibitor that interferes with Human Immunodeficiency Virus Type 1 gp160 processing. Antimicrob Agents Chemother 51(10): 3554-3561, 2007
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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