Wolan Laboratory The Scripps Research Institute Departments of Molecular and Experimental Medicine and Chemical Physiology
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Research Interests |
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Small Molecule Activators of ProenzymesVirtually all of the 560 human proteases are stored as inactive proenyzmes prior to regulated activation. As a postdoctoral fellow in the laboratory of Jim Wells (UCSF), Dennis Wolan identified and characterized the first synthetic small molecules that directly activate apoptotic procaspases. These compounds induce autoproteolytic activation of the proenzymes by stabilizing a conformation with increased enzymatic activity, as well as improve susceptibility to intermolecular proteolysis by upstream proteases. In a cellular setting, these procaspase activators promote rapid apoptosis and bypass the normal upstream intrinsic and extrinsic proapoptotic signaling cascades. Compounds that induce gain-of-function are rare and these activators presage the discovery of other proenzyme activators to explore fundamental processes of proenzyme regulation and activation in biology. Functional Proteomics of Human MicrobiomesAssociations between human microbial environments and the onset of human diseases are rapidly materializing. Elucidation of the symbiotic relationships that have evolved between humans and microbes, and of the associated diseases, will provide a wealth of invaluable information that can be exploited in drug discovery. The Wolan lab employs functional proteomics towards the identification of bacterial proteins implicated in disease and the subsequent discovery and iterative design of small molecule regulators of enzyme activity. Our ultimate goal is the moderation of microbiome distribution, activity and host responses via external small molecule intervention as potential foundations for the prevention and treatment of diseases.
Small Molecule Activity Regulators of Secreted Pathogenic Bacterial ProteasesProteases are widely expressed and secreted by both gram positive and negative bacteria and are required by bacteria for colonization, nutrient acquisition, host tissue damage and immune system evasion. As such, this class of proteins represent excellent targets for the identification and development of specific small molecule regulators. Initial targets for small molecule discovery in the Wolan lab include the well characterized cysteine proteases streptopain (Streptococcus pyogenes), clostripain (Clostridium histolyticum) and gingipains (Porphyromonas gingivalis). Streptopain activity has been implicated in pharyngitis (strep throat), cellulitis (skin rash) and necrotizing fasciitis as the protein targets degradation of extracellular matrix proteins important for tissue integrity, fibronectin and vitronectin. Likewise, streptopain promotes inflammation and septic shock by cleaving IL-1β to its mature form. Clostripain and gingipains are homologues of streptopain and are secreted cysteine proteases located in the gut and oral microbiomes, respectively, and have been linked to development of colonic lymphocytes and onset of periodontal disease. These proteases represent excellent targets for drug discovery as no known specific small molecule regulators have yet been discovered, and are also proof-of-principle targets that link human microbiota to disease. Specific lead activity modulators of these proteases could potentially be developed as therapeutics as well as probes for elucidating the roles that extracellular bacterial proteases play in human disease.
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