Bevirimat (formerly PA-457) was the first HIV-1 maturation inhibitor to enter clinical testing. The drug interferes with virus replication by blocking cleavage of the HIV Gag protein, which results in the production of defective virus particles that cannot infect new cells.

While bevirimat has demonstrated promising antiviral activity in clinical trials, Panacos has had trouble developing a formulation that delivers an adequate concentration of the drug, leading the company to increase doses in ongoing studies.

The company also launched a project to identify "second-generation" maturation inhibitors with reduced protein binding and more suitable pharmacokinetic profiles. While resistance to bevirimat has not yet been observed in patients, researchers also hoped to find a new agent with a distinct resistance profile.

At the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, taking place this week in Sydney, Australia, scientists from Panacos described a possible candidate agent meeting these requirements, PA1050040.

In laboratory studies, the effect of PA1050040 on HIV-1 Gag processing was assessed using Western blot assays. Standard viral inhibition assays were also performed. In vitro assays were conducted to determine the compound's cytotoxicity. Serum shift experiments were used to assess the effects of human serum protein binding on PA1050040 activity. Non-clinical pharmacology studies evaluated PA1050040's in vitro metabolic profile and investigated the compound's pharmacokinetics in rats.

Results

• PA1050040 specifically blocked p25 to p24 processing, similar to bevirimat.

• PA1050040 had a mean IC50 (50% inhibitory concentration) of 14.9 nM against HIV-1 prototypic and primary isolates

• The agent had a median in vitro CC50 (50% cytotoxicity) of > 50 uM.

• PA1050040 maintained potency against a panel of HIV-1 isolates resistant to the 4 classes of approved antiretroviral drugs (NRTIs, NNRTIs, protease inhibitors, and the fusion inhibitor enfuvirtide).

• PA1050040 retained wild-type activity against the bevirimat-resistant Gag mutant, L363M, but had reduced activity against another bevirimat-resistant mutant, A364V.

• PA1050040 exhibited approximately 8-fold lower human serum protein binding as compared to bevirimat.

• PA1050040 was glucuronidated in vitro by UGT1A1, 1A3, 1A4, and 1A8 and had minimal interaction with the CYP450 enzymes, suggesting it will have minimal interactions with other anti-HIV drugs.

• PA1050040 was orally bioavailable in rats with a half-life of 3 hours.

Conclusion

"PA1050040 warrants further development as a second-generation maturation inhibitor," the researchers concluded. "Reduced serum protein binding compared to bevirimat may yield greater potency in vivo.

"PA1050040 has a distinct in vitro resistance profile," they added. "Like bevirimat, PA1050040 maintains advantageous metabolic characteristics that may reduce the potential for metabolic drug-drug interactions."

Panacos Pharmaceuticals, Inc, Gaithersburg, MD.

07/24/07

Reference
N Kilgore, M Reddick, M Zuiderhof, and others. Characterization of PA1050040, a second generation HIV-1 maturation inhibitor. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Sydney, Australia, July 22-25, 2007. Abstract MOPDX05.

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