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	HEADLINES ARCHIVE MEDIA CENTER BLOG

November/December 2008

Discovery of Small Molecule Leads to New Hope for HIV Therapy

Ilene Raymond Rush November 1, 2008

New hope for combating HIV, the virus that leads to AIDS, comes from a small molecule discovered by researchers from the Laboratory of Molecular Virology directed by John Maga at the Institute of Molecular Genetics of the National Research Council of Pavia (IGM -CNR), in collaboration with the Laboratory of Pharmaceutical Chemistry, University of Siena, led by Professor Maurizio Botta, who is also an adjunct professor at the Sbarro Institute for Cancer Research and Molecular Medicine at the College of Science and Technology at Temple University in Philadelphia, PA.

The results, published in the Journal of Medicinal Chemistry from the American Chemical Society and reported on the la Repubblic.it web site (http://www.repubblica.it/2008/05/sezioni/scienza_e_tecnologia/hiv-nascita/aids-molecola/aids-molecola.html), show that blocking the action of the cellular enzyme DDX3 causes an interruption of viral replication in cells infected with the HIV virus without damaging uninfected cells, which have mechanisms to compensate for the loss of DDX3.

The small molecule is a pharmacologically active molecule, capable of blocking infection when directed against a cellular enzyme, unlike the current treatments based on drugs directed against viral enzymes.

"The HIV virus is a parasite of human cells, unable to reproduce outside the infected cells,” explains Dr. Maga. "As a true predator, the virus is introduced into the cell affected by infection (usually a lymphocyte blood cell) and drains the cell of its nutritional resources and energy to duplicate its genome and build new environs.

“At the end of this process of dispossession, the new virus leaves the cell, which exhausted of its resources, dies.”

Once the cell is infected, the HIV virus assumes control of several cellular enzymes, taking them away from their normal duties and "forcing" them to work to produce new viral particles.

"One of these enzymes is the cellular protein DDX3,” explains Dr. Maga, "which usually intervenes in the production of cellular proteins, facilitating the flow of genetic information between the nucleus (where the information is kept) and the cytoplasm (where the information is translated into new proteins). The HIV virus is part of this circuit and causes DDX3 to transport only the viral genetic information in order to maximize the production of viral proteins. So DDX3 is an essential cofactor for the reproduction of the virus in human cells."

On this basis, researchers have used computer techniques to design a molecule 'tailored' for then DDX3 protein. When synthesized and tested in biological tests, the molecule interferes with the action of DDX3, thus blocking the destructive process.

"These results demonstrate for the first time," the researcher added, "that a drug directed against a cellular enzyme is able to block HIV infection. Current anti-AIDS therapy is based drugs directed against viral enzymes.” But the viral enzymes have a tendency to change their structure during treatment, becoming resistant to drugs used.

"The cellular enzymes, however, have a much lower capacity to mutate," concludes John Maga, "so a drug directed against an enzyme in the cell was more likely to maintain its effectiveness for long therapy."