The Research Of Different Scaffolds Inserted Into The Disulfide Bond Of α-Conotoxins

Cono snails are a unique marine resource in the South China Sea,and the Conotoxins secreted by the snails is a great treasure of marine medicines.As the most widely studied conotoxins,α-Conotoxins act as competitive nicotinic acetylcholine receptors(n ACh Rs)antagonists.n ACh Rs as one kind of important receptors in human body,are widely expressed in muscles,central and peripheral nervous systems.Several n ACh Rs are involved in pathologies and disorders,including addiction,pain,depression,exercise,learning and cognition,etc.α-Conotoxins has excellent selectivity for various subtypes of n ACh Rs,therefore,α-Conotoxin can be developed as important tools for the physiological and pharmacological functions study of n ACh Rs,and it also has great value for the treatment of n ACh Rs-related diseases.Disulfide bonds,which determine the structure,activity,and selectivity ofα-Conotoxins,are easily destroyed by endogenous enzymes which affect its activity.Therefore,how to easily and efficiently modify the disulfide bonds of α-Conotoxins is an important scientific problem.In this project,17 α-Conotoxins were modified and41 analogues were synthesized.Most of them showed good inhibitory activity and selectivity against n ACh Rs.Among them,the selectivity of Cys[2,4] modified[A10L]Pn IA on n ACh Rs was improved,and the activities of Cys[2,4] modified Ls IA was maintained.In conclusion,Cys[2,4] can be used as a small molecule insertion site for 4/6 and 4/7 type α-conotoxins,while Cys[1,3] and Cys[2,4] can be the 3/5 typeα-Conotoxins modifiable site.In this study,small frameworks were used to bridge the disulfide bonds ofα-Conotoxins to construct the active conformation quickly and efficiently.This method not only solves the problems of low synthetic yield and mismatch of disulfide bonds of Conotoxins,but also achieves the connection between conotoxins with other molecules simultaneously.This is very important for the application of Conotoxin as fluorescent probe and targeted drug delivery.This method has great significance and value for the structure modification of α-Conotoxins and will pave the way for the exploitation and utilization of Conotoxins.