New protein target may advance design of HIV and cancer drugs

RICHMOND, Va. Using small molecules containing platinum, Virginia Commonwealth University Massey Cancer Center researchers have created a process to inhibit a class of proteins important in HIV and cancer.

The findings may help researchers develop new drugs to fight HIV or cancer by selectively targeting proteins known as zinc fingers.

In the May 30 issue of the journal Chemistry & Biology, researchers reported that a zinc finger protein, known as HIV NCp7, can be inhibited when it is exposed to a platinum complex. They observed that when the HIV NCp7 protein interacts with platinum, the zinc portion of the molecule is ejected from the protein chain. This causes the protein to lose its tertiary structure or overall shape. For these molecules, shape is an important property that enables the protein to carry out certain biological functions.

The process, active site displacement, involved design of a platinum drug with higher affinity for the protein peptide backbone, thus eliminating the zinc from its active site.

In the specific case discussed in the paper, the HIV NCp7 protein is responsible for the proliferation of the HIV virus. If researchers can inhibit the action of this zinc finger protein, they can stop the spread of the virus.

"When we target specific viruses with drugs, over time patients can become resistant to treatment and the drug becomes ineffective. Therefore, novel biological processes and proteins are attractive targets for antiviral drug development," said lead author Nicholas Farrell, Ph.D., professor and chair in the Department of Chemistry at VCU and a member scientist with the VCU Massey Cancer Center.

According to Farrell, these study findings may also one day be applied to the selective targeting of zinc fingers involved in the biological processes responsible for the spread of cancer. By applying the concept to development of anticancer drugs, the researchers hope to design more specific clinical agents with reduced side effects compared to the very useful, but toxic, cisplatin and congeners.

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This work was supported by a grant from the National Science Foundation and the American Cancer Society.

Researchers in the VCU departments of chemistry and biochemistry, and the VCU Institute for Structural Biology and Drug Discovery collaborated on this research. Researchers included A. I. Anzellotti, Ph.D., Q. Liu, Ph.D., M.J. Bloemink, Ph.D., and J. N. Scarsdale, Ph.D., who is also affiliated with Massey Cancer Center.

About the VCU Massey Cancer Center: The VCU Massey Cancer Center, one of 61 National Cancer Institute-designated research institutions, is VCU's focal point for basic and clinical cancer research, education, prevention and cancer health care. Since 1975, Massey has served as an internationally recognized center of excellence. Its 175 doctors and researchers are dedicated to improving the quality of human life by developing effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu.


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