Synthesis, biological activity, and conformational study of N-methylated allatostatin analogues inhibiting juvenile hormone biosynthesis.
An allatostatin (AST) neuropeptide mimic (H17) is a potential insect growth regulator, which inhibits the production of juvenile hormone (JH) by the corpora allata. To determine the effect of conformation of novel AST analogues and their ability to inhibit JH biosynthesis, eight insect AST analogues were synthesized using H17 as the lead compound by N-methylation scanning, which is a common strategy for improving the biological properties of peptides. A bioassay using JH production by corpora allata of the cockroach Diploptera punctata indicated that single N-methylation mimics (analogues 1-4) showed more activity than double N-methylation mimics (analogues 5-8). Especially, analogues 1 and 4 showed roughly equivalent activity to that of H17, with IC50 values of 5.17 × 10(-8) and 6.44 × 10(-8) M, respectively. Molecular modeling based on nuclear magnetic resonance data showed that the conformation of analogues 1 and 4 seems to be flexible, whereas analogues 2 and 3 showed a type IV β-turn. This flexible linear conformation was hypothesized to be a new important and indispensable structural element beneficial to the activity of AST mimics.
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.|‡Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario M5S 3G5, Canada.|§State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Company, Limited, Shenyang, Liaoning 110021, People's Republic of China.
Yong
Y
Xie
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.
Li
L
Zhang
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.
Chuanliang
C
Zhang
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.|‡Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario M5S 3G5, Canada.
Xiaoqing
X
Wu
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.
Xile
X
Deng
†Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, People's Republic of China.
Xinling
X
Yang
‡Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario M5S 3G5, Canada.
Stephen S
SS
Tobe
D000818:Animals; D003058:Cockroaches / Q000187:drug effects* / Q000378:metabolism; D003335:Corpora Allata / Q000187:drug effects / Q000378:metabolism; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007605:Juvenile Hormones / Q000096:biosynthesis*; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D015394:Molecular Structure; D009479:Neuropeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D007306:Insecticides; D007605:Juvenile Hormones; D009479:Neuropeptides; C076523:allatostatin
N-methylated allatostatin analogues; allatostatins; conformation; juvenile hormone biosynthesis; molecular modeling