Comparison of insect kinin analogs with cis-peptide bond motif 4-aminopyroglutamate identifies optimal stereochemistry for diuretic activity.
The insect kinins are present in a wide variety of insects and function as potent diuretic peptides, though they are subject to rapid degradation by internal peptidases. Insect kinin analogs incorporating stereochemical variants of (2S,4S)-4-aminopyroglutamate (APy), a cis-peptide bond motif, demonstrate significant activity in a cricket diuretic assay. Insect kinin analogs containing (2R,4R)-APy, (2S,4R)-APy and (2S,4S)-APy are essentially equipotent on an insect diuretic assay, with EC(50) values of about 10(-7)M, whereas the (2R,4S)-APy analog is at least 10-fold more potent (EC(50) = 7 x 10(-9)M). Conformational studies in aqueous solution indicate that the (2R,4S)-APy analog is considerably more flexible than the other three variants, which may explain its greater potency. The work identifies the optimal stereochemistry for the APy scaffold with which to design biostable, peptidomimetic analogs with the potential to disrupt critical insect kinin-regulated processes in insects.
Kaczmarek
Krzysztof
K
Areawide Pest Management Research Unit, Southern Plains Agricultural Research Center, ARS, U.S. Department of Agriculture, College Station, TX 77845, USA.
Williams
Howard J
HJ
Coast
Geoffrey M
GM
Scott
A Ian
AI
Zabrocki
Janusz
J
Nachman
Ronald J
RJ
D020816:Amino Acid Motifs; D000818:Animals; D001704:Biopolymers / Q000737:chemistry; D004231:Diuresis / Q000187:drug effects; D015195:Drug Design; D005260:Female; D006135:Gryllidae / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D019476:Insect Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D007313:Insecta / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D007705:Kinins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D013237:Stereoisomerism
C497085:4-aminopyroglutamate; D001704:Biopolymers; D019476:Insect Proteins; D007705:Kinins; D011761:Pyrrolidonecarboxylic Acid