848909-17-1Relevant academic research and scientific papers
Efficient synthesis of trypsin inhibitor SFTI-1 via intramolecular ligation of peptide hydrazide
Chen, Yi-Qun,Chen, Chen-Chen,He, Yao,Yu, Mu,Xu, Lin,Tian, Chang-Lin,Guo, Qing-Xiang,Shi, Jing,Zhang, Min,Li, Yi-Ming
, p. 2883 - 2886 (2014)
Cyclic peptide trypsin inhibitor SFTI-1 was synthesized via intramolecular ligation of a linear peptide hydrazide with high yield. This cyclization strategy did not cause epimerization at the C-terminal Arg residue. CD spectrum and NMR spectroscopy analysis demonstrated that well-folded SFTI-1 could be obtained via standard oxidative folding process. Thus, we present a simple and cost-efficient strategy for the synthesis of SFTI-1.
Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis
Nguyen, Giang K.T.,Wang, Shujing,Qiu, Yibo,Hemu, Xinya,Lian, Yilong,Tam, James P.
, p. 732 - 738 (2014)
Proteases are ubiquitous in nature, whereas naturally occurring peptide ligases, enzymes catalyzing the reverse reactions of proteases, are rare occurrences. Here we describe the discovery of butelase 1, to our knowledge the first asparagine/aspartate (Asx) peptide ligase to be reported. This highly efficient enzyme was isolated from Clitoria ternatea, a cyclic peptide-producing medicinal plant. Butelase 1 shares 71% sequence identity and the same catalytic triad with legumain proteases but does not hydrolyze the protease substrate of legumain. Instead, butelase 1 cyclizes various peptides of plant and animal origin with yields greater than 95%. With K cat values of up to 17 s -1 and catalytic efficiencies as high as 542,000 M-1 s-1, butelase 1 is the fastest peptide ligase known. Notably, butelase 1 also displays broad specificity for the N-terminal amino acids of the peptide substrate, thus providing a new tool for C terminus-specific intermolecular peptide ligations.
Application of tert-Butyl Disulfide-Protected Amino Acids for the Fmoc Solid-Phase Synthesis of Lactam Cyclic Peptides under Mild Metal-Free Conditions
Bierer, Donald,Chen, Jingnan,Chen, Junyou,Cui, Tingting,Guo, Yanyan,Li, Yi-Ming,Sun, Shuaishuai,Wang, Jun
, p. 8610 - 8619 (2021/07/19)
Lactam cyclic peptides are a class of interesting and pharmaceutically active molecules, but their previous syntheses have required the use of heavy metals and/or forcing conditions. Here, we describe the efficient application of the previously reported tert-butyl disulfide-protected amino acids and their use in the efficient, solid-phase synthesis of a series of lactam cyclic peptides under mild, metal-free conditions.
Expanding the scope of N → S acyl transfer in native peptide sequences
Cowper, Ben,Shariff, Leila,Chen, Wenjie,Gibson, Samantha M.,Di, Wei-Li,Macmillan, Derek
, p. 7469 - 7476 (2015/08/18)
Understanding the factors that influence N → S acyl transfer in native peptide sequences, and discovery of new reagents that facilitate it, will be key to expanding its scope and applicability. Here, through a study of short model peptides in thioester formation and cyclisation reactions, we demonstrate that a wider variety of Xaa-Cys motifs than originally envisaged are capable of undergoing efficient N → S acyl transfer. We present data for the relative rates of thioester formation and cyclisation for a representative set of amino acids, and show how this expanded scope can be applied to the production of the natural protease inhibitor Sunflower Trypsin Inhibitor-1 (SFTI-1).
Selective Bi-directional amide bond cleavage of N-methylcysteinyl peptide
Qiu, Yibo,Hemu, Xinya,Liu, Ding Xiang,Tam, James P.
, p. 4370 - 4380 (2014/07/21)
A selective bi-directional peptide bond cleavage mediated by N-methylcysteine (MeCys) in Xaa-MeCys-Yaa peptides (Xaa and Yaa, non-cysteine residues) leading to thioesters and thiolactones is described. Rate and product analyses showed that an Nα-amide bond cleavage occurred at the Xaa-MeCys bond by an N-S acyl shift to generate an Xaa-S-(MeCys-Yaa) thioester at pH 1-5, whereas under strongly acidic conditions of H0 = -5, the MeCys-Yaa bond underwent a Cα-amide bond cleavage via an oxazolone intermediate, which was trapped by thiocresol (TC) as an Xaa-MeCys-TC thioester. This thioester was then transformed into an Xaa-MeCys-β- thiolactone at pH 4-5. Replacing MeCys by a Cys residue did not result in significant bi-directional peptide bond cleavage, which suggests that N-methylation in a MeCys residue is important for the N-S acyl shift reaction and formation of oxazolone. The isomerization of amides and thioesters was successfully used to prepare cyclic peptides. Copyright
Between two worlds: A comparative study on in vitro and in silico inhibition of trypsin and matriptase by redox-stable SFTI-1 variants at near physiological pH
Avrutina, Olga,Fittler, Heiko,Glotzbach, Bernhard,Kolmar, Harald,Empting, Martin
supporting information, p. 7753 - 7762 (2013/05/09)
A comparative study on in vitro and in silico inhibition of trypsin and matriptase by derivatives of the sunflower trypsin inhibitor-1 at near physiological pH is reported. Besides wild-type bicyclic SFTI-1, monocyclic variants possessing native cystine as well as redox-stable triazolyl side-chain macrocyclization motifs were studied for the first time in matriptase inhibition assays. Interestingly, monocyclic SFTI-1[1,14] demonstrated higher potency against this pharmacologically relevant protease compared to its bicyclic counterpart. Structural analysis of binding/inhibition of investigated SFTI-1 derivatives was performed using a combination of molecular dynamics simulations and docking experiments. In silico data were in good accordance with in vitro results, indicating the importance of the terminal inhibitor regions for the affinity towards matriptase. Presented work gives new perspectives for the optimization of the SFTI-1 framework towards in vivo applications. The Royal Society of Chemistry 2012.
