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Bio
My goal is to understand and treat disease at the atomic level. During a Ph.D. in inorganic chemistry I learned high-resolution mass spectrometry and advanced spectroscopic methods (Raman, magnetic circular dichroism, electron paramagnetic resonance spectroscopy). My thesis contains seminal biochemical/mechanistic work on the biosynthesis of iron-sulfur clusters and proposed the mechanism of IscU, one of nature's most conserved proteins. Post-doctoral studies in neurotoxicology provided an understanding of ALS etiology and the tools to determine whether a disease-related change was toxic or protective, i.e. to differentiate epiphonema from cause and define potential treatments. The first decade of my independent research was dedicated to discovering ALS-related modifications of proteins and their functional consequences, and was consistently funded by the NIH. This required the development of mass spectrometry (MS) methods, including over 20 collaborative manuscripts involving “top-down” MS or MALDI MS imaging and over 20 manuscripts applying these methods ALS. We also developed diverse numerical modeling methods, including models of protein aggregation kinetics, familial SOD1 ALS epidemiology, and isotopic fine structure. Together the kinetic model and epidemiological models (now popular tools for researchers of other neurologic disorders) provided strong evidence that aggregation of SOD1 was toxic in ALS patients, i.e., a rationale for developing pharmacological chaperone to stabilize fALS SOD1 variants. We invented cyclic thiosulfinate crosslinkers for this purpose. These novel compounds, utilizing a novel cross-linking mechanism, were repeatedly deemed too risky as a therapeutic strategy by NIH review panels. Nonetheless, I focused the laboratory on their development, secured alternative funding, hired industry experts in drug development, and maintained a laboratory of 6-10 Ph.D. students. Backed by IND-enabling data we return to the fray to seek support for preclinical testing of cyclic thiosulfinates. The four publications below demonstrate the debut of cyclic thiosulfinate mediated crosslinking (Donnelly 2018); a quantum mechanical model of cyclic thiosulfinate mechanism (Donnelly 2019a); methods for intact protein analysis (Donnelly 2019b); and cyclic thiosulfinate-mediate hydrogel synthesis (Aluri K 2020).
Research Interests
Papers共 117 篇Author StatisticsCo-AuthorSimilar Experts
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PLoS biologyno. 1 (2024): e3002462-e3002462
Nature reviews. Methods primersno. 1 (2024): 1-23
Research squarepp.1-9, (2023)
Cancer Researchno. 12_Supplement (2022): 2322-2322
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