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ID: ALA4665791
Journal: J Med Chem
Title: Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.
Authors: Lin L,Olson ME,Sugane T,Turner LD,Tararina MA,Nielsen AL,Kurbanov EK,Pellett S,Johnson EA,Cohen SM,Allen KN,Janda KD
Abstract: Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and in vitro evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.
CiteXplore: 32886509