The Duerfeldt laboratory integrates synthetic/medicinal chemistry, chemical and structural biology, and computational methods to develop chemical probes and therapeutic leads for unexploited targets implicated in pathogenesis. Ongoing research programs include:
Biological Significance and Therapeutic Value in Bacterial Pathway/Enzyme Activation
The continued rise of drug resistance, paired with the decline in newly approved antibiotics for existing targets, has reinvigorated the desire to exploit new antibacterial strategies. Our approach aims to identify both natural product and small molecule modulators that cause detrimental effects to bacteria through pathway or enzyme activation, rather than inhibition. Currently, we are interested in developing new molecules that activate bacterial proteases or two-component signaling pathways.
Small Molecule Permeation and Accumulation in Gram-negative Bacteria
A major roadblock to the development of novel antibiotics is our poor understanding of the structural features of small molecules that correlate with bacterial premeation and accumulation. As a result, while potent biochemical inhibitors can often be identified for new targets, developing them into compounds with whole-cell antibacterial activity has proven challenging. As such, the development of quantitative tools to predict small-molecule penetration and efflux in bacteria would have a major impact on antibacterial drug discovery, enabling rational approaches to library design and hit-to-lead optimization. In collaboration with researchers at Sloan Kettering, OU, and industry partners we are working to address this need for predictive capability.
Small Molecule Treatments for Diabetic Retinopathy
Currently, over 400 million people worldwide have diabetes mellitus. Nearly 1/3 of diabetics suffer from diabetic retinopathy (DR), a leading cause of blindness in the global working population. Despite standard treatment options, the ability to address the microvascular component of DR remains a significant challenge. While anti-VEGF therapy demonstrates good efficacy in the clinic, this mode of intervention suffers from a dependence on iterative injections, high cost (U.S. = $1.5 B in 2008-09), limited access in developing countries, and a heavy burden to healthcare infrastructures. As such, the global prevalence of DR continues to rise and a critical need exists to develop low cost, readily available, systemic treatments. In collaboration with the Oklahoma University Health Science Center, we are developing new therapeutic modalities to address DR and mechanistically related conditions (e.g., age-related macular degeneration. retinopathy of prematurity.