New chemicals to inhibit HIV infection

In corporation with peers from the Mount Sinai School of Medicine, New York University, researchers from the University of Science and Technology of China (USTC), a CAS affiliate, have come up with new chemical inhibitors against HIV reproduction, marking a significant progress in the development of anti-AIDS drugs based on natural host resistance.

Since the start of the HIV epidemic, a series of drugs have been developed which significantly prolong the lives of people who are HIV positive. However, the rapid mutation of drug-resistant human immunodeficiency virus type 1 (HIV-1) poses severe challenges to the drug development.

Unlike the conventional ways of aiming at a viral protein per se, reported Prof. Wang Zhiyong from USTC and Prof. MingMing Zhou from Mount Sinai of School Medicine in a recent issue of the Journal of American Chemical Society, the novel anti-Aids approach they have taken is to target the host cell proteins essential for the virus to replicate.

In order for HIV-1 reproduction to be initiated, according to the experts, the viral protein Tat, a viral regulatory protein required for HIV-1 replication, must interact with a protein found in the host cell called the PCAF, which normally functions to help convert human genes into human proteins. The researchers use nuclear magnetic resonance to define the structure of this interaction, and design and synthesize three small molecules that would bind to PCAF, preventing its interaction with Tat and ultimately preventing HIV from reproducing.

The findings offer new insight into the most effective approach for fighting the AIDS disease. Specifically the studies show that compounds designed for the PCAF bind selectively with high affinity to the site shared with the HIV-Tat protein, which could inhibit Tat's binding, thus abolishing the transcriptional activation and replication of HIV-1 and working as a potential therapeutic drug. The advantage of targeting a host protein is that drug resistance is less likely to develop than with drugs that target viral proteins.

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