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Targeted HIV protein leads to new drugs

27-Sep-2004

The recent surge in HIV research shows no sign of terminating as researchers reported the successful targeting of an HIV protein that has eluded existing therapies. The technique used for identifying the synthetic molecules may also lead to new drug therapies with improved treatment options.

The discovery could pave the way in treating a disease that has killed over 20 million people worldwide. Current treatment remains largely expensive with no guarantees of success. Currently the nucleoside reverse transcriptase inhibitors (RTIs), non-nucleoside RTIs and HIV protease inhibitors remain the most popular forms of treatment.

Use of these drugs in combination has had dramatic impact on patients' survival, but the development of resistance is still a major cause of treatment failure.

Researchers targeted Nef, a protein responsible for accelerating the development of the HIV virus into AIDS. The researchers looked for a mechanism that would disrupt binding by Nef and found that their synthesized molecules and Nef both competed to bind with the cellular proteins. Competition for the binding sites dislodged Nef from binding to the three cellular proteins and thus inhibited.

Gregory Weiss, lead researcher at the University of California, Irvine, said: "By proving small molecules can be effective for targeting Nef, we've shown how researchers can expand the fight against AIDS."

In addition, the researchers invented a system for identifying guanidine alkaloids - small molecule inhibitors of protein-protein interactions. They attached the Nef protein to the surface of a bacteriophage (a virus whose host is a bacterium), which provided a 'handle' that could be tracked by the researchers to determine whether Nef was binding to three cellular proteins.

This is the first time phage display has been used to identify molecules that disrupt protein-protein interactions.

While the method was successful, Weiss said the molecules identified proved toxic to cells. He is now seeking to develop less toxic compounds with high potencies against Nef without causing collateral damage.

"A key benefit of this achievement," he added, "would be the development of therapies using smaller molecules, which can often be used in oral medications. Therapies that rely on larger molecules are used in medications injected by needle."

The spread of HIV is a phenomenon that seems to be going from bad to worse. A study presented in 2003 showed that 10 per cent of newly-infected HIV patients in Europe had contracted a strain of the virus that was already resistant to at least one antiretroviral drug, while the majority of patients who have been on therapy for a while harbour resistant strains. It is recognised that avoiding resistance - more than side effects and dosing profile - is the key to long-term success of HIV therapy.

The researchers reported their findings last week in the online edition of the Proceedings of the National Academy of Science. The print version of the research paper will appear in the Sept. 28 issue of the journal.

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