Public Release: 

GlaxoSmithKline Drug Discovery and Development Research Grant Program 2003

$500,000 in research grants awarded to researchers working toward breakthroughs in HIV/AIDS drug therapies

Public Communications Inc.

Research Triangle Park, N.C. (November 20, 2003) - Five researchers have been awarded 2003 GlaxoSmithKline (GSK) Drug Discovery and Development Research Grants for their efforts to develop new pharmaceutical strategies to combat HIV, the virus that causes AIDS. The recipients, who will share $500,000 in grant money, are: Paul Bieniasz, Ph.D., Associate Professor, Aaron Diamond AIDS Research Center, New York City; Michael Farzan, Ph.D., Assistant Professor, Brigham and Women's Hospital, Boston; Michael Malim, Ph.D., Professor, King's College London, U.K.; Wei Zhang, Ph.D., Senior Scientist, Fluorous Technologies Inc., Pittsburgh; and Ming-Ming Zhou, Ph.D., Associate Professor, Mount Sinai School of Medicine, New York City.

"We are honored to recognize and support the creativity and scientific excellence of these outstanding researchers, whose novel strategies for defeating HIV renew the hope of one day bringing the HIV pandemic to an end, and strengthen our ongoing commitment to the research and development of pharmaceutical therapies against HIV," said Doug Manion, M.D., vice president of clinical development and medical affairs for GSK.

The recipients were announced during the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago in September.

An Expert Review Board, composed of researchers who are leaders in the field of HIV/AIDS, independently judged and selected the award recipients. John A. Bartlett, M.D., professor of medicine at Duke University Medical Center; David D. Ho, M.D., professor at Rockefeller University and scientific director at Aaron Diamond AIDS Research Center; and Michael Saag, M.D., associate professor of medicine and director of the AIDS Outpatient Clinic at the University of Alabama at Birmingham, served on the board this year.

A New System for Screening Compounds in Pharmaceutical "Libraries"

Paul Bieniasz, Ph.D., was awarded a $125,000 Drug Discovery and Development Research Grant for his research into the use of genetic screening methods to evaluate the potential anti-HIV properties of cyclic peptides.

"We theorize that random cyclic peptide libraries are likely to contain members that exhibit anti-HIV activity, but there has been no large scale, systematic screen of these libraries for inhibitors of HIV," Dr. Bieniasz said. Peptides are compounds comprising two or more amino acids, the building blocks of proteins. "Cyclic" peptides have one or more rings formed by peptide links, a bond that stabilizes the compounds and makes them less likely to break down.

Currently, most compounds are tested with a method called high-throughput screening, in which large numbers of molecules are individually synthesized and tested against a number of viral targets. The assay of each compound tested also must be physically separate from the assays of other compounds in the library.

"With genetic screening methods there will be no need to separate each peptide from the library, which will enable us to screen in combination many diverse compounds," he said.

A New Strategy to Inhibit HIV Entry into Host Cells

Michael Farzan, Ph.D., received a $125,000 Drug Discovery and Development Research Grant for his research into compounds called tyrosine-sulfated peptides and their potential to inhibit HIV entry into the human host cell.

"The entry of HIV into its target cells requires expression of the receptor CD4, a protein on the surface of human T cells, and also of a co-receptor protein embedded in the membrane of the cell," Dr. Farzan said.

Proteins which act as co-receptors for HIV are CCR5 are CXCR4. The first step in HIV entry takes place when glycoprotein "spikes," which include a protein called gp120 bind with the host cell receptor CD4. This triggers changes in gp120 that, in turn, enable the virus to attach to a co-receptor and complete the binding process. Dr. Farzan and colleagues have previously shown that this binding is dependent on tyrosine sulfate groups on the co-receptor.

"The peptides which are the focus of our research appear to function as effective mimics of one or more of the co-receptors needed to complete HIV binding and entry into the host cell," said Dr. Farzan.

Among the aims of the research conducted by Dr. Farzan and his co-investigators is to further characterize variants of tyrosine-sulfated peptides, and test the ability of compounds based on these peptides to attach to the co-receptor binding site on gp120, thereby blocking the co-receptor needed for viral entry into the host cell.

Inhibition of the HIV Vif Gene

Viral infectivity factor (Vif), a regulatory protein expressed by HIV, plays a critical role in HIV infection by blocking CEM15/APOBEC3G (CEM15) - an anti-retroviral protein in the human host cell that specifically sabotages the virus's ability to replicate.

"Pharmacological strategies to inhibit Vif is a logical and attractive approach in the search for novel anti-HIV therapies," said Michael H. Malim, Ph.D., who received a $125,000 Drug Discovery and Development Research Grant for his research to better understand the biochemical properties and structures of Vif and CEM15, and the ways in which the two proteins interact.

Professor Malim and other scientists in his research group were the first to describe the anti-HIV properties of the CEM15 protein, which is packaged into the HIV progeny virions, or proviruses, that bud from virus-infected host cells and are released to infect other human cells. In the absence of Vif, CEM15 alters the chemical composition of deoxycytidine, a constituent of viral DNA, thereby disabling viral replication and stopping the spread of HIV.

"Both Vif and CEM15 are structurally unique compared to other proteins of their type, and neither is yet well understood," Dr. Malim said. It is hoped that the research will lead to new drugs that target the interaction of VIF/CCEM15, and also will provide information about other HIV gene products and their human cellular co-factors.

A New Approach to Inhibiting HIV Reverse Transcriptase

Many of today's approved anti-retroviral drugs work by inhibiting reverse transcriptase (RT), the enzyme needed to convert viral RNA into DNA, enabling the virus to integrate its genetic material into the DNA of the human host cell.

Nucleoside and nonnucleoside RT inhibitors now on the market work by inhibiting RT's polymerase activity, which is to copy the genetic materials needed to infiltrate the human cell. The DNA copy, however, remains associated with the original viral RNA, forming what's called an RNA/DNA complex.

"To proceed with replication, the virus must degrade the RNA component, a process carried out by another portion of the RT enzyme called Ribonuclease H (RNase H). "Currently, there are no approved anti-retrovirals that inhibit this vital step of HIV replication," said Wei Zhang, Ph.D.

Dr. Zhang was awarded a $62,500 Drug Discovery and Development Research Grant to test compounds called mappicine analogs that may comprise a promising new class of HIV RNase H inhibitors. This work will be carried out with Co-Investigator Michael Parniak, Ph.D., of the University of Pittsburgh.

Mappicine is a natural derivative of the plant Mappia Feotida. It is hoped that a mappicine analog will prevent HIV RNase H from degrading the RNA component of the RNA/DNA duplex intermediate, thereby preventing HIV replication. Similar chemical derivatives that inhibit topoisomerase, enzymes responsible for the arrangement of DNA in cancer cells and for cell growth and replication, are being investigated as anticancer drugs.

"By targeting a different stage of RT activity, Ribonuclease H inhibitors also may be effective in treating HIV that has developed resistance to conventional RT inhibitors," Dr. Zhang said.

A New Strategy to Inhibit Tat

Tat is a regulatory protein of HIV which plays a role in shielding reservoirs of dormant HIV-infected cells from cytotoxic T-Lymphocytes (CTLs). CTLs - naturally occurring "killer" cells of the immune system - resist infection by HIV because the virus cannot bind to the receptors on the surface of CTLs as they can with those of other T-cells of the immune system. Tat appears to act like a shield, protecting reservoirs of HIV-infected cells and playing a role in activating latent reservoirs of the virus.

"Our recent studies show that activation of HIV transcription and viral replication requires an interaction between Tat and a human cellular protein called PCAF, a co-activator in the transcription process," said Ming-Ming Zhou, Ph.D.

"Our goal is to develop chemical inhibitors that selectively interfere with the interaction of Tat and PCAF, a strategy that may intervene and stop the process of HIV gene expression and replication," said Dr. Zhou.

Dr. Zhou was awarded a $62,500 Drug Discovery and Development Research Grant to pursue ongoing research into Tat/PCAF interaction and the design of chemical compounds that may inhibit the interaction.

"Targeting PCAF - the host cell protein - rather than the HIV cell protein as a strategy to block HIV gene expression has several advantages," Dr. Zhou said. "Perhaps the most important is that the human host cell and its proteins cannot mutate. This could reduce or eliminate the problem of drug resistance, which results from HIV's ability to mutate rapidly."

Since the inception of the Drug Discovery and Development Research Grant program in 2001, GSK has awarded $1.25 million to further the development of inventive treatments for HIV/AIDS, including therapies aimed at treating infection, as well as prophylactic vaccines or microbicides designed to prevent transmission of the virus. The program allows GSK to foster independent research without placing limitations on the creative process.

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For detailed information about the Drug Discovery and Development Research Grant Program, interested applicants can visit http://www.dddresearchgrant.com or call 1-888-527-6935.

GlaxoSmithKline is a pharmaceutical industry leader in HIV research and therapies. The company is engaged in basic research programs designed to investigate new targets to treat HIV. In addition to GlaxoSmithKline's Drug Discovery and Development Research Grant Program, the company also provides grants to community based organizations that provide services to those whose lives are most affected by HIV.

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