RESEARCH DESCRIPTIONThe main focus of this laboratory is drug discovery and development. The students who work on these projects will be trained in organic synthesis, spectroscopy, molecular modeling, in-silico virtual screening, lead identification, structure activity relationship studies, lead optimization, in vitro enzyme kinetic assays and cell based assays. The ongoing projects are listed below.
Anticancer Drug Discovery
The past decade has witnessed an immense increase in the development and clinical use of potent anticancer agents with novel structures. Many of these drugs function by interacting with DNA and more specifically by modulating the activities of the nuclear enzymes such as topoisomerase I and topoisomerase II. These enzymes are responsible for generating necessary topological and conformational changes in DNA and are critical to many cellular processes such as replication and transcription. Topoisomerases have been classified into type I and II based on their ability to produce transient protein mediated single strand or double strand breaks. Topoisomerase inhibitors interfere with the breaking and rejoining reactions of these enzymes by trapping an abortive enzyme-DNA cleavable complex. Such inhibition of mammalian topoisomerases has been recognized as an effective approach for developing cancer chemotherapeutic agents.
Our group is looking at compounds of both natural and synthetic origin as potential source for developing topoisomerase I and II inhibitors. Historically, natural products have provided many successful new anti-cancer drugs (eg: doxorubicin, etoposide, taxol, gemcitabine). For the past quarter of a century, global marine sources have provided a vast array of new medicinally valuable natural products with anticancer activities. These natural products exist as secondary metabolites in marine invertebrates such as sponges, bryazoa, tunicates and ascidians. Several new experimental anticancer agents derived from marine natural products have entered advanced pre-clinical and clinical trials within the last decade. We are specifically working on developing new anti breast cancer agents derived from marine alkaloids that have shown inhibition of topoisomerase II.
S. aureus causes a variety of human infections, ranging from superficial abscesses to life threatening bacteremias. Staphylococcal infections within the hospital and in the community are increasing, and an ever-growing number of antibiotic-resistant strains make treatment options difficult. Many of the nosocomial Methicillin-resistant S. aureus (MRSA) strains are multi-drug resistant, and even methicillin-sensitive strains can be deadly. Notorious as a major source of nosocomial infections, S. aureus has recently taken on a new role in causing an escalating number of community-acquired infections in non-hospitalized persons without predisposing risk factors. New approaches for the prevention and treatment of bacterial infections require greater understanding of the molecular structures of the chosen intervention targets and of the pathogenic role played by the target in the infection process. 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. Sortase-deficient strains, failing to anchor surface proteins, are found to be attenuated in their virulence. Hence, sortase is an attractive potential target for the discovery of new antibacterial agents. 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.
Sadanandan E. Velu, Associate Professor of Chemistry, obtained his MS degree at the University of Calicut (1985) and obtained his Ph.D. degree in Organic Chemistry at the University of Madras (1993). He did his postdoctoral research at the University of Alabama and at Clemson University. Dr. Velu joined the medicinal chemistry division of the Center for Biophysical Sciences and Engineering of UAB in 1997 and worked as a staff scientist until 2004. He also held a joint appointment in the UAB Department of Chemistry as a research faculty during 2002-2004. He joined the chemistry department as an Assistant Professor in August of 2004. Dr. Velu was tenured and promoted to Associate Professor rank in 2010.