Novel Chemical Approaches to Protein Targeting and Detection

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Our research program focuses on using organic/bioinorganic chemistry to develop innovative molecular solutions to fundamentally difficult disease-related problems. The research can be placed in two categories: A) Medicinal chemistry, where we seek to develop novel chemical architectures for the recognition and inhibition of biologically relevant molecules; B) Molecular recognition, where we seek to develop novel diagnostic tools for molecular biomarkers of disease/infection. For the proposed discovery grant, we will focus on the following research topics: 1) Targeting the electrophile-reactive proteome with novel covalent therapeutics. We and others have utilized the reactive electrophile, pentafluorobenzenesulfonamide (PFBS), to modify nucleophilic residues on target proteins. For example, Batabulin, a PFBS-containing molecule modifies a Cys residue in the colchicine binding site of B-tubulin to prevent microtubule formation. However, Batabulin reacts rapidly with the Cys-containing glutathione (GSH) and loses efficacy. Here, we propose a different strategy for rescuing the utility of PFBS and limiting its activity against GSH. - A novel electrophilic warhead platform: spectrum of reactivity. A major goal of our work is to create a toolkit of warheads with selective reactivity profiles for every type of nucleophile. To this end, building on new chemistry developed in our lab, we propose to develop novel tetra-fluorobenzene sulfonamides, substituted in the 6-position with a spectrum of electron donating and withdrawing groups to vary reactivity. Our goal is to explore this novel chemistry and establish an armory of novel warheads. 2) Design and applications of novel excimer-based turn-on fluorescent sensors for bacterial detection in sterile fluids. Rapid diagnosis of infections of blood and cerebrospinal fluid (CSF) remains a highly unmet clinical need. Currently, diagnosis can only be achieved in a minimum of 24 hours, owing to the need of culturing bacteria samples to enable their detection. Here, we aim to develop a novel diagnostic tool for rapid (< 20 min) detection of blood and CSF infections. At the core of our technology is a novel class of highly sensitive fluorescent chemical sensors, which selectively detects as few as 10 bacterial cells using a conventional fluorometer. We will chemically optimize the sensors and develop the most suitable methods for signal detection.