New Therapeutic Agents and Approaches
Drug Design, Discovery and Development
The Chemistry Department at Georgia State Univeristy has a tradition of strong programs in drug discovery and development. This area is strongly connected to Biosensors and Diagnostics, and Biomolecular Structure and Interactions focus areas and to research programs in the Biology and Psychology Departments.
Dr. Bing Wang has added extensive expertise in drug discovery to the program. He is editor in chief of Medicinal Research Reviews, which has been ranked #1 two years in a row in Impact Factor among 36 medicinal chemistry journals. The Department has taken a leadership role in new approaches to identification and treatment of disease, and members of the Department are active in the Molecular Biology of Disease Program and the Center for Biotechnology and Drug Design.
Faculty members in this group recognize that drug discovery and development is an interdisciplinary process with medicinal chemistry at its core. Emphasis is placed on promoting interdisciplinary collaboration aimed at eventually developing therapeutic agents. Since drug discovery generally begins with selection of a target, the drug discovery and development effort naturally overlaps with our Biomolecular Interactions focus area. Research groups are looking at both nucleic acid targets and protein targets.
Dr. Dabney Dixon is studying the proteins that are involved in heme uptake in the bacteria, with a focus on the lipoprotein that delivers heme to the ABC transporter in Streptococcus pyogenes. This work is in collaboration with Dr. Zehava Eichenbaum of the Biology Department. Because some microorganisms get most of their iron from heme, and because some of the proteins are known to be antigenic, inhibition of these proteins offers an effective potential therapeutic strategy. Dr. Giovanni Gadda’s research focus is on choline oxidase and choline dehydrogenase.
Dr. Jenny Yang is working both on the nonstructural proteins in rubella virus (in collaboration with Dr. Teryl Frey in Biology) and on proteins involved in the immune response of poxvirus. Some patients with severe depression are refractory to treatment with antidepressants. The ability to predict this at the start of treatment would greatly help these patients.
Dr. Kathy Grant is investigating the biochemical basis for this non-responsiveness using molecular biology techniques.
Dr. Irene Weber is working on molecular models of human glucokinase to understand the effects of mutations associated with diabetes and other glycemic diseases. Her work with HIV and cancer is described above.
In the synthetic medicinal chemistry and drug development areas, Dr. David Boykin has brought international renown to the Department with his synthetic work on amidines. In early studies, a molecule designed and made in his laboratory (DB289) proved better than the current clinical treatment for some fungal infections.
DB289 has also been very successful in treating Human African Sleeping Sickness. Dr. Boykin and a consortium of researchers were recently awarded $15.1 million from the Bill & Melinda Gates Foundation to develop these compounds. Clinical trials on this agent are now in Stage III and new trials on additional compounds and diseases are scheduled.
Dr. Lucjan Strekowski’s work on the synthesis of molecules that interact with DNA focuses on defining the stereoelectronic factors that control the interaction of DNA with groove-binding molecules as well as stabilization of the double-, triple-, and quadruple-helix structures of DNA. Dr. Strekowski is also working on a practical synthetic route to a novel, highly potent anti-migraine drug.
His rational design of Toll-like receptor 9 (TLR-9) antagonists has resulted in a patent that was recently licensed by GSU to Coley Pharmaceutical Group. He has also designed and synthesized iminosulfuranes as novel skin penetration enhancers and the membrane effects of these enhancers is being studied by Dr. Jerry Smith.
Very recently, Dr. Strekowski has synthesized a series of compounds that are novel, highly selective antagonists of 5-HT7 receptor. This work may provide the basis for the development of new drugs against depression.
Dr. Baumstark’s work on oxygen-atom transfer reagents has lead to useful synthetic approaches to epoxidation and heteroatom oxidation. Dr. Dabney Dixon is part of a team developing vaginal microbicides to protect women against infection by HIV in collaboration with scientists from Emory University, Louisiana State University, Tampa Bay Research Institute and FemmePharma, Inc. Other work in the Dixon group has concentrated on investigating metal-based DNA-binding compounds in conjunction with radiation as a new approach to cancer chemotherapy.
This goal of this work (in collaboration with Dr. Brenda Laster, Israel) is to create clustered damage in tumor DNA. The Wang lab has several drug discovery projects. Through structure-based design, the Wang lab is working on developing sub-family selective phosphodiesterase 4 (PDE4) inhibitors as potential anti-asthma agents. They are also developing antimicrobial agents against drug-resistant strains by targeting the efflux pumps. In collaboration with oncologist Brent Weston (UNC-CH), development strategies for targeted drug delivery to cancer cells based on their molecular biomarkers is in progress. Among the many promising lead compounds, one PDE4 inhibitor is ready for animal testing for asthma treatment.