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3926414
Masked cerulenin enables a dual-site selective protein crosslink
Date
August 13, 2023
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In the current study of polyketide and non-ribosomal peptide biosynthesis, a major goal has been the structural elucidation of the megasynthases that produce them. We have been developing chemical biology tools to study these enzyme systems, with a focus on dual site-selective crosslinking probes. Protein-reactive natural products such as the fungal metabolite cerulenin are recognized for their value as therapeutic leads due to the ability to selectively react with catalytic residues within a protein active site or protein complex. Here, we explore the development of fatty-acid and polyketide synthase probes by synthetically adapting the reactive functionalities of cerulenin. Using a mechanism-based approach, we further develop and reveal unique reactivity within cerulenin and adapt it for fluorescent labeling and crosslinking select proteins within fatty acid and iterative type I polyketide synthases. Inclusive in this study are two new classes of silylether cyanohydrin and hemiaminal masked crosslinking probes, which offer new tools for activity and structural studies of these pathways.
My lab uses ‘Applied Chemical Biology’ to develop novel therapeutic modalities. Enzyme inhibition has proven to be a successful paradigm for pharmaceutical development, however, it has several limitations…
Chemical probes are powerful tools for characterizing protein function, which offer the advantages of producing graded effects (both agonism and antagonism) and acute application, features that are well suited to the study of essential genes and post translational processes…
Small molecules that induce functional proximity between two protein partners have driven a revolution in drug-discovery, however, understanding the pharmacology of these new modalities poses a challenge, as their effects diverge from traditional inhibitor-based drugs…