Dr. Scott D. Pegan’s on-going research intent is centered on discovering new classes of drug candidates for use in antiviral, antibiotic, and cancer therapies. We use a complementary approach that utilizes advanced structural biology, biophysical and enzymatic techniques as well as the latest in high-throughput screening methodology. Our intent is to discover pharmaceuticals that are not only disease specific, but can also be developed for broad based applications.
Regulation of the Human Innate Immune System
To gain a greater understanding of the mammalian innate immune response and how it is modulated, as well as develop new therapeutic templates for emerging diseases. Our on-going intent is to investigate the anti-viral type I response through the structural and kinetic study of proteases and ligases involved in the immune response signaling pathway. Through this research a better understanding of the role these proteins play in cellular regulation of the innate anti-viral immune response will occur. Currently, we are working with a model system from Crimean-Congo Hemorrhagic Fever virus (CCHFV), which in itself is a dangerous emerging pathogen exhibited by its recent deadly outbreaks in Turkey and India. Furthermore, CCHF has spread across Asia and Africa and is present particularly in the Middle East transmission. Danger to US was highlighted in 2009 by the death of a US Soldier serving in Afghanistan by CCHFV.
Discovering the Source of Genetic Disease in Adenylosuccinate Lyase Deficiency
Adenylosuccinate Lyase Deficiency is a disease of purine metabolism which affects patients both biochemically and behaviorally. The symptoms are variable and include psychomotor retardation, autistic features, hypotonia, and seizures. Although some studies of mutant ADSL enzyme activity and stability have been carried out, successfully correlating the residual enzyme activity with the severity of the disease has been met with limited success, obstructing the identification of affected individuals and treatment of the disorder. To remedy this situation, Dr. Pegan is currently collaborating with Professor David Patterson (DU, Biology) and Assistant Professor Kingshuk Ghosh (DU, Physics) to carry out a comprehensive biophysical and biochemical analysis of specific mutations that give rise to ADSL deficiency in order to develop an initial predictive model of ADSL severity. This project combines three DU faculty members’ expertise and spans three DU departments: Dr. David Patterson’s knowledge and previous pioneering DU research into ADSL deficiency, my extensive structural biology expertise that includes elucidation of the molecular mechanism behind Andersen’s Syndrome, and Dr. Kingshuk Ghosh’s computational expertise in developing predictive computation models of proteins.
Discovery of new antibiotics for use against Tuberculosis
Tuberculosis (TB) is one of the most prevalent infections in the world, and a leader among the causes of mortality in developing countries. The World Health Organization estimates one third of the world’s population is infected with latent TB. With a rise in new cases of active TB and emergence of multidrug resistant strains, MDR-TB and XDR-TB, there is a strong need for development of antibiotics targeting novel pharmacological targets within Mycobacterium tuberculosis. One such drug target for TB is M. tuberculosis’ class II fructose 1,6-bisphosphate aldolase (MtFBA), which is required for bacterial survival and is non-existent in humans. Inhibitors have been developed for class II FBAs; however, they lack specificity and drug-like properties, preventing their translation into viable therapeutic leads. Optimization of these compounds has been historically hindered by a lack of MtFBA structural information. Recently, we elucidated the structures of an important novel drug target, MtFBA by itself, bound with substrates and bound with a inhibitor. The latter inhibitor bound structure has offered a unique approach to MtFBA inhibition. Additionally, by enzymatic screening of a small compound library, two drug-like chemical scaffolds have been identified that possess inhibitory properties against both MtFBA and TB. Our intent is to use these new structures to optimize preliminary drug candidates we have uncovered to yield novel chemical compounds that have potent anti–bacterial features for therapeutics targeting TB and other pathogenic bacteria.