Small atrial natriuretic peptide analogues: design, synthesis, and structural requirements for guanylate cyclase activation.
Structure/activity studies on atrial natriuretic peptide ANP (1-28) have highlighted three portions of the native molecule as necessary for its biological responses. We have linked these three regions and excised the remaining segments to produce a family of small analogues (less than half the size of the parent) which demonstrate the full range of ANP's actions. Importantly, these compounds act at both major types of ANP receptor. Two critical modifications lead to more potent analogues; both involve expanding the cyclic portion of the molecule. Further optimization of one of these modified structures leads to A68828, a full ANP agonist which shows promise as a preventative agent against acute renal failure.
von Geldern
T W
TW
Cardiovascular Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Rockway
T W
TW
Davidsen
S K
SK
Budzik
G P
GP
Bush
E N
EN
Chu-Moyer
M Y
MY
Devine
E M
EM
Holleman
W H
WH
Johnson
M C
MC
Lucas
S D
SD
D058186:Acute Kidney Injury / Q000517:prevention & control; D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D006152:Cyclic GMP / Q000096:biosynthesis; D004231:Diuresis / Q000187:drug effects; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009318:Natriuresis / Q000187:drug effects; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000378:metabolism; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C066680:A 68828; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP