STa peptide analogs for probing guanylyl cyclase C.
Guanylyl cyclase C (GC-C), universally overexpressed on primary and metastatic colorectal carcinoma cells, is activated by endogenous ligands, guanylin, and uroguanylin, and by exogenous 18-residue heat-stable enterotoxins (STa) produced by diarrheagenic bacteria. Two 12-residue STa analogs with alternate combinations of two interlocked disulfide bonds, peptides 3 and 6, were synthesized by orthogonal solid phase synthesis routes. Peptides 3 and 6 bound GC-C with a rank order potency of STa > peptide 3 > peptide 6. Peptides 3 and 6 behaved as agonists in stimulating cGMP production. The results reveal that the toxic domain of STa can be reduced to 12 amino acids.
Tian
Xiaobing
X
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Michal
Allison M
AM
Li
Peng
P
Wolfe
Henry R
HR
Waldman
Scott A
SA
Wickstrom
Eric
E
D000595:Amino Acid Sequence; D000818:Animals; D001427:Bacterial Toxins / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000201:enzymology / Q000382:microbiology; D004220:Disulfides / Q000378:metabolism; D016503:Drug Delivery Systems; D004768:Enterotoxins / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000175:diagnosis / Q000201:enzymology; D029968:Escherichia coli Proteins; D006162:Guanylate Cyclase / Q000138:chemical synthesis / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000378:metabolism*
D001427:Bacterial Toxins; D004220:Disulfides; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D010455:Peptides; D018000:Receptors, Peptide; C034151:heat stable toxin (E coli); D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled