Natural Product Inspired Drug Design
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:
PATHWAY/ENZYME ACTIVATION AS AN ANTIBACTERIAL STRATEGY
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 TREATMENTS FOR DIABETIC RETINOPATHY
Currently, over 400 milion 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.
SCALABLE SYNTHESIS OF 3-D BIOCORES
While commercial screening libraries have successfully provided therapeutic hits/leads for a number of drug targets including GPCRs, ligand-gated ion channels and kinases, lower success rates have been observed for antibacterial targets and targets identified from genomic studies. Recently, a number of studies have been published suggesting that the planar characteristics of molecules in widely available screening libraries is a major culprit for inactivity against certain targets. As such, there is a need to develop fragment libraries that contain scaffolds rich in 3-dimensional character. We utilize creative synthetic methodology to provide access to 3-D rich natural product fragments; therefore simultaneously contributing to the expansion of screening libraries and advancement of synthetic methodology.
Research keywords: medicinal chemistry; synthesis; chemical biology