The goal of the Molecular Aspects of Drug Design Section is to discover new approaches to the design of drugs against cancer and viral diseases, especially AIDS. The general strategy is to integrate information obtained from biological and molecular studies of disease development with structural data on potential drug targets to design new drugs with greater effectiveness and lower systemic toxicity. Our specific approach is to combine mechanistic, computational, and synthetic chemistry with biochemical and biological studies of the candidate drugs. The ability to repair DNA damage is critical to the survival of a cell, whether normal or cancerous. Thus, in principle, specific repair processes in tumor cells may offer novel and highly selective targets for drugs. We have found that bisimidazoacridones and the closely related bistriazoloacridones (collectively referred to as BIAs), which were discovered in our laboratory, are potently cytostatic to human colon cancer cells in tissue culture and inhibit tumor growth in nude mice. Although the BIAs are not cytotoxic, they do cause cell cycle arrest at the G1 and G2 checkpoints. We have recently found that the arrested cells can be pushed into apoptosis by the cdk inhibitors, such as UCN-01. Since BIAs have low systemic toxicity but high selectivity, the combination regimen may prove to be a useful chemotherapeutic tool. Extensive biophysical measurements on BIAs in solution and in the presence of nucleic acids led to the conclusions that the compounds bind to DNA by monointercalation, with the remaining chromophore and the linker being loosely associated with a groove. Some BIAs were found to be potent inhibitors of HIV. The antiviral BIAs appear to specifically target a component of transcriptional initiation, a novel molecular target for HIV. The targeting of drugs to specific receptors on tumor cells is a conceptually attractive method to enhance specificity and to decrease systemic toxicity. We have chosen the gastrin receptor (GR) as a prototype to test this hypothesis. Gastrin, the ligand for GR, is a readily modifiable peptide hormone. We have attached several cytotoxic moieties to various gastrin-derived peptides. Some of these conjugates have been shown to be very cytotoxic to GR+ cells but relatively benign in GRu cells. The results of these studies should be applicable to many other receptors. The techniques used for measuring trafficking of GR have been applied successfully to study the trafficking of other G-protein-coupled receptors (GPCR), such as the cholecystokinin receptor type A and the chemokine receptors CXCR4 and CCR5. Additionally, we have found that the function of GPCRs can be inhibited in a novel manner. Peptides corresponding to the sequence of the individual transmembrane (TM) domains, which also contain anionic substituents on the extracellular termini, were able to disrupt the function of their cognate receptors. For example, the second TM domain of the chemokine receptor CXCR4 was able to completely block signaling through the receptor and to prevent HIV-1 entry into receptor-positive cells. We also showed that the same principle could be applied to the inhibition of function of other proteins that contain multiple membrane-spanning domains, such as the multiple drug resistance protein P-gp. Reverse transcription of the HIV RNA genome by reverse transcriptase (RT) is a required step in viral replication. Thus, RT has been an attractive target for drug design. Unfortunately, effective inhibitors of wild-type HIV RT are usually rapidly rendered ineffective by mutations in the enzyme. We have been searching for a new generation of inhibitors that will be active against mutant forms of RT. Our approach utilizes a combination of structural and molecular modeling studies that guide structure-directed synthesis. the efficacyof new inhibitors is determined by a variety of cell-based and biochemical assays.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010347-03
Application #
6763642
Study Section
(SBL)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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