Up to 80 per cent of HIV positive people on treatment show resistance to one or more of their drugs, according to Graham Allaway of Panacos Pharmaceuticals in Gaithersburg, Maryland, which is developing PA-457. Panacos hopes to begin trials this month to test how well the drug works in patients whose existing drug regimes are failing.
PA-457 aims to overcome this resistance by attacking HIV on new front. Many existing drugs work by blocking reverse transcriptase, an enzyme that enables HIV to replicate within cell. Others disable protease, which helps to assemble the virus into particles that infect other cells.
Recent experiments in collaboration with Michael Sakalian and his colleagues at the University of Oklahoma Health Sciences Center in Oklahoma City have shown that PA-457 works in a different way. It attacks HIV by disrupting formation of a conical shield, called the capsid protein, which stores and protects the RNA heart of the HIV particles as they bud out from infected cells.
The latest research, in which the virus was examined under a microscope, shows that the drug binds to the capsid protein at acrucial stage in its manufacture (Journal of Virology, vol 80, p 5716). Normally, the capsid protein is clipped apart from a major structural protein called the gag protein, and is then assembled into a cone. PA-457 stops it being clipped off, causing it to form a leaky sphere that leaves the core RNA exposed (see Diagram, left). This cripples the virus, preventing it from infecting any other cells once it buds out from the host.
Previous lab experiments on infected human cells