Cyclotides constitute a fascinating family of circular proteins containing ca.30 amino acid residues.They have a unique cyclic cysteine knot topology and exhibit remarkable thermal,chemical and enzymatic stabilities.T...Cyclotides constitute a fascinating family of circular proteins containing ca.30 amino acid residues.They have a unique cyclic cysteine knot topology and exhibit remarkable thermal,chemical and enzymatic stabilities.These characteristics enable them to have a range of biological activities and promising pharmaceutical and agricultural applications.Here,we present a practical strategy for the chemical synthesis of cyclotides through the intramolecular ligation of fully unprotected peptide O-esters.This strategy involves the mild Fmoc solid-phase peptide synthesis of the peptide O-ester backbone,the head-to-tail cyclization of the cyclotide backbone by native chemical ligation,and the oxidative refolding to yield the natural knot protein.The simplicity and high efficiency of the strategy can be employed in the synthesis of artificial cyclotides for pharmaceutical applications.展开更多
The mechanism for the decomposition of 2-mercaptoethyl O-ester was theoretically investigated.The mecha-nism that 2-mercaptoethyl O-ester undergoes an S_(N)2 displacement of the O atom by the S atom onα-C is much fa-...The mechanism for the decomposition of 2-mercaptoethyl O-ester was theoretically investigated.The mecha-nism that 2-mercaptoethyl O-ester undergoes an S_(N)2 displacement of the O atom by the S atom onα-C is much fa-vored over the mechanism of N-to-S acyl transfer.The length of the alcohol moiety has large effects on the decom-position efficiency of thiol-substituted alkyl O-esters.The reactivities of these esters are controlled by distortion en-ergies.Only 2-mercaptoethyl O-ester can undergo the decomposition at room temperature due to the low distortion energy to achieve the transition state geometry.If the thiol group of 2-mercaptoethyl O-ester is replaced by an amino group,the N-to-N acyl transfer mechanism is more favored than the S_(N)2 displacement mechanism.展开更多
基金supported by the National Natural Science Foundation of China(20932006,91013007)the National Basic Research Program of China(973 Program)(2011CB965300)
文摘Cyclotides constitute a fascinating family of circular proteins containing ca.30 amino acid residues.They have a unique cyclic cysteine knot topology and exhibit remarkable thermal,chemical and enzymatic stabilities.These characteristics enable them to have a range of biological activities and promising pharmaceutical and agricultural applications.Here,we present a practical strategy for the chemical synthesis of cyclotides through the intramolecular ligation of fully unprotected peptide O-esters.This strategy involves the mild Fmoc solid-phase peptide synthesis of the peptide O-ester backbone,the head-to-tail cyclization of the cyclotide backbone by native chemical ligation,and the oxidative refolding to yield the natural knot protein.The simplicity and high efficiency of the strategy can be employed in the synthesis of artificial cyclotides for pharmaceutical applications.
基金We thank the National Natural Science Foundation of China(No.21202102)for the financial support.
文摘The mechanism for the decomposition of 2-mercaptoethyl O-ester was theoretically investigated.The mecha-nism that 2-mercaptoethyl O-ester undergoes an S_(N)2 displacement of the O atom by the S atom onα-C is much fa-vored over the mechanism of N-to-S acyl transfer.The length of the alcohol moiety has large effects on the decom-position efficiency of thiol-substituted alkyl O-esters.The reactivities of these esters are controlled by distortion en-ergies.Only 2-mercaptoethyl O-ester can undergo the decomposition at room temperature due to the low distortion energy to achieve the transition state geometry.If the thiol group of 2-mercaptoethyl O-ester is replaced by an amino group,the N-to-N acyl transfer mechanism is more favored than the S_(N)2 displacement mechanism.
