Targeting the guanylate cyclase c receptor with an agonist peptide from enterotoxegenic Y. Enterocolitica [abstract]
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Heat-stable enterotoxin peptides (ST's) are expressed by enterotoxigenic strains of bacteria in order to co-opt an endogenous ligand-receptor system that regulates fluid homeostasis within the gut. Bacteria such as E. coli, V. Cholerae, and Y. enterocolitica have evolved ST's which mimic native guanylin/uroguanylin peptides by activating guanylate cyclase C (GC-C), yet possess increased resistance to heat/enzymatic degradation as well as superagonist activity by virtue of a third disulfide bond. We have previously utilized ST peptides derived from an E. coli isolate, as well as analogs of the endogenous peptide hormone uroguanylin, as imaging and therapeutic agents for GC-C-expressing colorectal cancers. In this work, we have compared the ability of these peptides to target GC-C and engender production of cGMP with that of an ST analog derived from Yersinia enterocolitica. Previous results had suggested that the Y. enterocolitica sequence may elicit higher cyclase activity than other peptides in this class. We have generated the peptide GENDWDWCCELCCNPACFGC both with and without an N-terminal DOTA chelating moiety and characterized its receptor binding affinity and ability to stimulate cGMP production in comparison to other peptides in this class. Our findings indicate that the Yersinia peptide possesses receptor binding affinity and cyclase stimulating activity intermediate between known E. coli ST analogs and human uroguanylin. However, in vivo biodistribution results obtained using the 64Cu-labeled DOTA-peptide demonstrated normal tissue distributions substantially different from E. coli-derived peptides, and more akin to those obtained with radiolabeled uroguanylin peptides.