Effector protein YopH represents an attractive drug target due to the potential use of Y. pestis as a bioterrorism agent. The first KM optimization of a library of nitrophenylphosphate-containing substrates was used for generating an inhibitor lead against YopH. A high activity substrate identified by this method (KM = 80 �M) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the in silico docking studies and furanyl-based oxime derivatives were identified as providing favorable interactions with target residues. By this process, a potent (IC50 = 190 nM) and selective YopH inhibitor was developed. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The approach may afford significant utility beyond its immediate target.

Nitrophenylphosphate substrate screening and oxime-based ligation for the development of nanomolar affinity inhibitors of the <i>Yersinia pestis</i> protein tyrosine phosphatase YopH

243rd National Meeting (2012)

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Nitrophenylphosphate substrate screening and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH