Velu Lab Research
Anti-Breast Cancer Agents from Marine Alkaloids
The chemotherapeutic agents currently used to treat breast cancer often have severe side effects and thus decrease the quality of life for the patients. Although new “rationally-targeted therapies” such as anti-estrogens have helped increase survival rates, their effects are limited to sub-populations of patients. For example, aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) affect only estrogen-receptor positive (ER+) cancer cells, which account for only half of all breast cancers. In spite of the recent advances in computational approaches for lead identification and drug discovery, natural products remain an important source of novel anticancer agents. In addition, natural products provide drugs with unprecedented molecular structures and bioactivity that are often inaccessible by other methods, and provide a template for future drug design. Our laboratory has focused recent research on the development of novel marine natural products and their analogs for human breast cancer therapy.
Inhibitors of Staphylococcus aureus Sortase A
Bacterial infections are very complex and involve the action of a large sophisticated arsenal of virulence factors, many of which are surface-bound. Surface proteins are one such virulence factor that plays a critical role in the infection process. The enzyme sortase catalyzes transpeptidation between sorting signals present in surface proteins destined to the bacterial surface and cross-bridge peptides in a cell wall precursor known as lipid II. We hypothesize that Sortase inhibitors will render S. aureus nonadherent and consequently less virulent. By interrupting bacterial adherence, the initial step in the pathogenesis of bacterial infections, S. aureus will be poorly equipped to cause disease and may be more effectively cleared by host innate immune defenses and/or antibiotics. As bacterial pathogens develop resistance to conventional antibiotics, inhibition of bacterial surface protein display offers a novel strategy against S. aureus bacterial infections.
Inhibitors of Trypanosoma Cruzi Dihydrofolate Reductase
Chagas’ disease is caused by the protozoan parasite Trypanosoma cruzi, which is primarily transmitted by an insect vector. No drug is effective in treating the chronic phase of this disease, and those used for treatment of the acute phase of the disease result in serious toxic side effects. Since the dihydrofolate reductase (DHFR) activity of T. cruzi (TcDHFR) is essential for the parasite, it represents a potential target for rational drug design. While DHFR is a monofunctional protein in mammals, T. cruzi and other protozoan parasites carry a bifunctional form of the enzyme in which the DHFR domain is linked to the thymidylate synthase (TS) domain with a linker sequence whose length varies from one parasite to the other. In order to facilitate rational design of a selective inhibitor of the T. cruzi DHFR we have initiated a structure based drug design using the X-ray crystal structure of T. cruzi DHFR. Subtle differences in the active sites of T. cruzi DHFR and human T. cruzi DHFR are taken in to consideration in order to design more selective and potent inhibitors of T. cruzi DHFR.
Discovery of Voltage-Gated Sodium Channel Blockers
Significant success has been achieved for treating localized (primary) cancers. But, subsequent metastasis to often involving multiple tissues remains responsible for >90% of cancer related deaths, in spite of aggressive therapy. The ability to prevent or slow down metastasis would represent a major breakthrough in cancer therapy and dramatically improve life expectancies of cancer patients. Fortunately, our increasing understanding of the metastatic process has recently resulted in the discovery of new potential drug targets to prevent / slow metastasis. One such target is the voltage-Gated Sodium Channel (VGSC). VGSCs are dramatically upregulated in a number of highly aggressive metastatic cancers. This project is directed towards targeting VGSCs for developing drugs that prevent / slow down breast and prostate cancer metastasis.
Investigating Suppression Therapy to Treat MPS I-H
Rare genetic diseases are thought to affect approximately 25 million people in the United States, and roughly 2.5 million of these individuals have diseases caused by Premature Termination Codons (PTCs). The pharmacological suppression of PTCs has shown promise in the treatment of patients with some genetic diseases caused by these mutations. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the abundance of transcripts carrying PTCs, has the potential to significantly reduce the effectiveness of this approach. In this study, we hypothesize that simultaneous inhibition of NMD and suppression of a disease-causing PTC will provide a synergistic increase in the amount of protein (and function), leading to a greater overall therapeutic effect. The successful development of this combined therapeutic approach has the potential to improve the quality of life of many individuals with a wide range of genetic diseases.
Discovery of Novel Potential Promutagenic Substrates for SULT2B1b
Sulfation of promutagens is a frequent mechanism for the generation of electrophilic compounds that may be cytotoxic. Almost all human SULTs have been shown to bio-activate a variety of promutagens including hydroxymethyl polyaromatic hydrocarbons and N-hydroxy-aromatic amines. Our collaborator’s laboratory has recently demonstrated that SULT2B1b is over-expressed in human glioblastoma and high-grade astrocytoma brain tumors. The selective expression of SULT2B1b in these tumors allows for the identification or development of agents that are selectively bio-activated by SULT2B1b and can be used as agents to selectively treat glioblastoma and astrocytoma.
Novel Mitochondrially Targeted Antioxidant Therapeutics
Ethanol induced hepatotoxicity is a complex process involving major changes in both the redox status of the cell and hemodynamic alterations that affect hepatic blood supply. Responses to chronic ethanol consumption include increased sensitivity to hypoxia and to cytokines such as TNF-?. In this project we build on our recent findings that define a role for peroxynitrite in contributing to hypoxic stress leading to steatosis in ethanol-dependent hepatotoxicity. We are trying to demonstrate that a mitochondrially targeted antioxidants can ameliorate steatosis. We are currently in the process of
designing a novel series of mitochondrial therapeutics designed to examine this therapeutic potential.