STU BORMAN

An HIV inhibitor in preclinical development turns out to have a unique mechanism of action against a novel viral target. It could become the first example of a new class of AIDS drugs: maturation inhibitors.

A research team characterizing the anti-HIV drug candidate 3-O-(3',3'-dimethylsuccinyl)betulinic acid (PA-457) found that the drug acts by disrupting a late stage of viral maturation--processing of HIV's Gag protein, which forms the capsid around the virus's RNA-based genome and establishes a functional viral core structure. Treated viral particles develop defective core structures and are noninfectious.

The work was carried out by Chief Science Officer Carl T. Wild and coworkers at Panacos Pharmaceuticals, Gaithersburg, Md., in collaboration with researchers at the National Institute of Allergy & Infectious Diseases and George Washington University Medical Center [Proc. Natl. Acad. Sci. USA, published online Oct. 22, http://www.pnas.org/cgi/doi/10.1073/pnas.2234683100]. "No one has previously identified a clinical development candidate that targets HIV assembly and maturation," Wild tells C&EN.

Preclinical studies indicate PA-457 is orally bioavailable and works in synergy with approved HIV drugs. The company hopes to soon file an application with FDA to begin clinical trials.

"The real significance of compounds with novel mechanisms of action is their utility in patients where drug resistance has developed," Wild notes. "PA-457 potently inhibits virus strains resistant to approved HIV drugs. These findings suggest that PA-457 may one day provide a new treatment option for the increasing number of patients infected by drug-resistant strains of HIV."

VIRAL IMMATURITY PA-457 inhibits HIV maturation, resulting in a noninfectious virus with a malformed core. © 2003 PANACOS PHARMACEUTICALS