The lethal factor (LF) enzyme secreted by <i>Bacillus anthracis </i>is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies have been conducted toward the design of small-molecule LF inhibitors, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2’ subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogs specifically designed to extend into, and probe chemical preferences of, this S2<b>′</b> subsite. We discovered that this region accommodates a wide variety of chemical functionalities, and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity.  We also present key residues in this subsite that can potentially be targeted to improve inhibitor binding.

Probing the S2 subsite of the anthrax toxin-lethal factor

251st National Meeting (2016)

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