A peptide-based fluorescence resonance energy transfer assay for Bacillus anthracis lethal factor protease.

Cummings, Richard T; Salowe, Scott P; Cunningham, Barry R; Wiltsie, Judyann; Park, Young Whan; Sonatore, Lisa M; Wisniewski, Douglas; Douglas, Cameron M et al. · Proc Natl Acad Sci U S A · 2002

basic_science · Level V

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Abstract

A fluorescence resonance energy transfer assay has been developed for monitoring Bacillus anthracis lethal factor (LF) protease activity. A fluorogenic 16-mer peptide based on the known LF protease substrate MEK1 was synthesized and found to be cleaved by the enzyme at the anticipated site. Extension of this work to a fluorogenic 19-mer peptide, derived, in part, from a consensus sequence of known LF protease targets, produced a much better substrate, cleaving approximately 100 times more efficiently. This peptide sequence was modified further on resin to incorporate donor/quencher pairs to generate substrates for use in fluorescence resonance energy transfer-based appearance assays. All peptides cleaved at similar rates with signal/background ranging from 9-16 at 100% turnover. One of these substrates, denoted (Cou)Consensus(K(QSY-35)GG)-NH(2), was selected for additional assay optimization. A plate-based assay requiring only low nanomolar levels of enzyme was developed for screening and inhibitor characterization.

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