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桥连双环肽作为潜在的药物骨架：合成、结构、蛋白质结合及稳定性

Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability.

作者信息

Bartoloni Marco, Jin Xian, Marcaida Maria José, Banha João, Dibonaventura Ivan, Bongoni Swathi, Bartho Kathrin, Gräbner Olivia, Sefkow Michael, Darbre Tamis, Reymond Jean-Louis

机构信息

Department of Chemistry and Biochemistry , University of Berne , Freiestrasse 3 , 3012 Berne , Switzerland . Email:

School of Life Sciences , Ecole Polytechnique de Lausanne , 1015 Lausanne , Switzerland.

出版信息

Chem Sci. 2015 Oct 1;6(10):5473-5490. doi: 10.1039/c5sc01699a. Epub 2015 Jul 13.

DOI:10.1039/c5sc01699a
PMID:29861888
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5949603/
Abstract

Double cyclization of short linear peptides obtained by solid phase peptide synthesis was used to prepare bridged bicyclic peptides (BBPs) corresponding to the topology of bridged bicyclic alkanes such as norbornane. Diastereomeric norbornapeptides were investigated by H-NMR, X-ray crystallography and CD spectroscopy and found to represent rigid globular scaffolds stabilized by intramolecular backbone hydrogen bonds with scaffold geometries determined by the chirality of amino acid residues and sharing structural features of β-turns and α-helices. Proteome profiling by capture compound mass spectrometry (CCMS) led to the discovery of the norbornapeptide binding selectively to calmodulin as an example of a BBP protein binder. This and other BBPs showed high stability towards proteolytic degradation in serum.

摘要

通过固相肽合成获得的短线性肽的双环化用于制备与桥连双环烷烃（如降冰片烷）拓扑结构相对应的桥连双环肽（BBP）。通过氢核磁共振、X射线晶体学和圆二色光谱对非对映异构的降冰片肽进行了研究，发现它们代表了由分子内主链氢键稳定的刚性球状支架，其支架几何形状由氨基酸残基的手性决定，并具有β-转角和α-螺旋的结构特征。通过捕获化合物质谱（CCMS）进行蛋白质组分析，发现降冰片肽作为BBP蛋白结合剂的一个例子，能选择性地与钙调蛋白结合。这种和其他BBP在血清中对蛋白水解降解表现出高度稳定性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/9553e1289d4e/c5sc01699a-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/37d63b548123/c5sc01699a-s1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/0931a78afa5b/c5sc01699a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/c5a9dc7541f2/c5sc01699a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/6c5399586c07/c5sc01699a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/0b73afb49e2e/c5sc01699a-s2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/1d88946a8b17/c5sc01699a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/150729b0fd41/c5sc01699a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/9553e1289d4e/c5sc01699a-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/37d63b548123/c5sc01699a-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/0cda754ab315/c5sc01699a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/ae3dcc0d8230/c5sc01699a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/0931a78afa5b/c5sc01699a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/c5a9dc7541f2/c5sc01699a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/6c5399586c07/c5sc01699a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/0b73afb49e2e/c5sc01699a-s2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/1d88946a8b17/c5sc01699a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/150729b0fd41/c5sc01699a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78a2/5949603/9553e1289d4e/c5sc01699a-f8.jpg

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