Development of a selective peptide antagonist for the human natriuretic peptide receptor-B.
Activation by C-type natriuretic peptide (CNP) of its receptor NPRB results in venodilation and inhibition of cellular proliferation. NPRB-selective antagonists should be useful to understand their physiological implications. We previously observed that [Thr9,Ser11,Arg16](N,C-ANP)pBNP (P12) is an antagonist for bNPRB and a potent agonist for bNPRA. The antagonist [Ser11](N-CNP,C-ANP)pBNP(2-26) (P18) displays six-fold selectivity towards hNPRB versus hNPRA. Deletion of the C-terminus in [Ser11](N-CNP,C-ANP)pBNP(2-25) (P19) decreases its affinity for hNPRA but improves its selectivity 35-fold. Peptide libraries based on P19 using phage display methodology yielded two positive clones P20 and P21. P19 behaves as the most potent antagonist, but P20 is the most selective.
Deschênes
Julie
J
Department of pharmacology, Faculty of Medicine, Université de Montréal, Montréal, Qc, Canada, H3T 1J4.
Duperé
Cécile
C
McNicoll
Normand
N
L'Heureux
Nicholas
N
Auger
François
F
Fournier
Alain
A
De Léan
André
A
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology; D006162:Guanylate Cyclase / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D045283:Natriuretic Agents / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018000:Receptors, Peptide / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D000099242:Atrial Natriuretic Factor Receptor B
D006152:Cyclic GMP; D006162:Guanylate Cyclase; D045283:Natriuretic Agents; D009419:Nerve Tissue Proteins; D019151:Peptide Library; D010455:Peptides; D017461:Receptors, Atrial Natriuretic Factor; D018000:Receptors, Peptide; D000099242:Atrial Natriuretic Factor Receptor B; C073616:atrial natriuretic factor receptor C