Clusters: Chemical Biology, Infectious Diseases, Microbiology, Small Molecule Drug Discovery

Roger Linington, Department of Chemistry and Biochemistry

Dr. Linington’s natural products and organic chemistry lab focuses on two complimentary areas of neglected infectious disease research: identification of novel drug leads against malaria and cholera, and development of natural products as chemical probes to explore questions of basic biochemistry in the arena of parasitology. Natural products are a crucial component of todays therapeutic arsenal and exploration of the diversity present in microbes from marine sediments represents an exciting new avenue for contemporary drug discovery. (Keywords: marine natural products, chemical genetics, drug discovery, infectious disease, malaria, cholera, leishmaniasis, chagas, parasitology)

Figure 1. General lab strategy. Figure 2.Target ID using Bifunctional NP Chemical Probes.

Research during the ‘golden age’ of antibiotic drug discovery in the 1980’s highlighted the wealth of bioactive chemotypes available from soil-derived microorganisms. As an extension of this biogenetic resource, the Linington lab is exploring the microbial diversity of marine sediments for their ability to produce novel drug leads. By employing environmentally relevant isolation and fermentation conditions, the lab is identifying novel isolates with activity against a range of neglected infectious disease targets.

Neglected Infectious
Disease Drug Discovery

Due to the high economic cost of developing new drugs, there has been little effort by the pharmaceutical industry in tackling diseases, such as malaria and cholera, which effect predominantly third world nations. The Linington group, in collaboration with Dr. Fitnat Yildiz at UCSC and Dr. Dennis Kyle at USF, is looking for novel clinically relevant treatments for neglected infectious disease targets, including cholera, malaria, leishmaniasis and Chagas disease. By developing new peak library strategies for fractionating microbial extracts and HTS screening strategies, they are aiming to develop rapid and efficient methodologies for the identification of new chemotypes with activities against this panel of orphan diseases.

Natural Products as Chemical Probes

Two major challenges in biomedicine in the post-genomic era are the determination of drug targets (mode of action) and the understanding of individual protein function. Chemical genetics is well placed to address both of these questions by exploiting specific small molecule-protein interactions. The Linington lab is developing novel bifunctional chemical probes to address these questions by applying the specific and highly potent biological activities of many natural products to give targets. By interfacing the unique NP libraries at UCSC with this new probe technology, they are developing methods for the delineation of biological processes considered to be essential for pathogenic virulence.