Structure-activity relationships for Periplaneta americana hypertrehalosemic hormone. I: The importance of side chains and termini.
Single amino acid replacement analogues for the native hypertrehalosemic hormone I of the American cockroach, Periplaneta americana (Pea-CAH-I: pGlu-Val-Asn-Phe-Ser-Pro-Asn-Trp-NH2), have been prepared by solid-phase peptide synthesis, and complete dose-response curves have been measured in P. americana monitoring the carbohydrate-mobilizing activity in vivo. All analogues that elicited hypertrehalosemia showed similar time-response courses, indicating that transport and degradation rates were comparable. Comparison of the potency and efficacy parameters of the analogues under study in the dose-response curves revealed four activity groups: 1) analogues that had the aromatic amino acids at positions 4 (phenylalanine) or 8 (tryptophan) replaced by alanine and glycine, respectively, had trace activity; 2) analogues with alanine at positions 1 or 2 had low potencies and an apparent biphasic dose-response relationship without much observable loss of efficacy; 3) analogues with glycine at positions 6 and 7 had potencies and efficacies most similar to Pea-CAH-I; and 4) analogues that had either an alanine instead of asparagine residue at position 3, or had a substitution of the carboxylamide function at the C-terminus by a carboxyl function reached apparent saturation, but only achieved 50-57% of the maximum activity of the native peptide. The potency profile for the analogue set is consistent with the importance of the N-terminal pentapeptide and the C-terminal tryptophan interacting with receptor(s) more closely than the side chains at positions 6 and 7, which are predicted to be the corner residues of a beta-turn. Finally, the biphasic dose-response curves observed for more than one analogue suggest the potential that receptors for Pea-CAH-I exist in more than one form.
Gäde
G
G
Zoology Department, University of Cape Town, Rondebosch, South Africa.
Hayes
T K
TK
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D004305:Dose-Response Relationship, Drug; D006458:Hemolymph / Q000378:metabolism; D007301:Insect Hormones / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D010526:Periplaneta / Q000737:chemistry / Q000187:drug effects*; D017433:Protein Structure, Secondary; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014199:Trehalose / Q000378:metabolism*
D007301:Insect Hormones; D009479:Neuropeptides; D010455:Peptides; C043192:glutamyl-valyl-asparaginyl-phenylalanyl-seryl-prolyl-asparaginyl-tryptophanamide; D014199:Trehalose