The development of protease inhibitors has received great attention due to the importance of proteases in the regulation of various cellular processes. Peptide-based aldehydes exhibit inhibitory activities against a variety of proteases and proteasomes in the context of anti-proliferative treatments for cancer, Alzheimer's and other diseases. More than a dozen peptide-based aldehyde natural products have been discovered (i.e. chymostatin, leupeptin and fellutamide); however, the biosynthetic origin of the aldehyde functionality has yet to be elucidated. Herein we describe the discovery of a new group of lipopeptide aldehydes, the flavopeptins, and the corresponding biosynthetic pathway arising from an orphan gene cluster in Streptomyces sp. NRRL-F6652, a close relative of Streptomyces flavogriseusATCC 33331. Flavopeptins are synthesized by a nonribosomal peptide synthetase containing a terminal NAD(P)H dependent reductase domain�leading to the reductive release of the peptide with a C-terminal aldehyde. Solid phase peptide synthesis of several flavopeptin species enabled structural verification and subsequent screening of biological activity. Flavopeptins exhibited micromolar to nanomolar inhibition activities against cysteine proteases and the human 20S proteasome as well as anti-proliferative activities against multiple myeloma and lymphoma cell lines.

Proteomics guided discovery of flavopeptins: Antiproliferative lipopeptide aldehydes released by an NAD(P)H dependent NRPS reductase domain

246th National Meeting (2013)

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