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RISS 인기검색어
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- 저자 : Kutchukian, Peter S. (검색결과 1 건)
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Stitched α-Helical Peptides via Bis Ring-Closing Metathesis
Hilinski, Gerard J.,Kim, Young-Woo,Hong, Jooyeon,Kutchukian, Peter S.,Crenshaw, Charisse M.,Berkovitch, Shaunna S.,Chang, Andrew,Ham, Sihyun,Verdine, Gregory L. American Chemical Society 2014 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.136 No.35
<P>Conformationally stabilized α-helical peptides are capable of inhibiting disease-relevant intracellular or extracellular protein–protein interactions <I>in vivo</I>. We have previously reported that the employment of ring-closing metathesis to introduce a single all-hydrocarbon staple along one face of an α-helical peptide greatly increases α-helical content, binding affinity to a target protein, cell penetration through active transport, and resistance to proteolytic degradation. In an effort to improve upon this technology for stabilizing a peptide in a bioactive α-helical conformation, we report the discovery of an efficient and selective bis ring-closing metathesis reaction leading to peptides bearing multiple contiguous staples connected by a central spiro ring junction. Circular dichroism spectroscopy, NMR, and computational analyses have been used to investigate the conformation of these “stitched” peptides, which are shown to exhibit remarkable thermal stabilities. Likewise, trypsin proteolysis assays confirm the achievement of a structural rigidity unmatched by peptides bearing a single staple. Furthermore, fluorescence-activated cell sorting (FACS) and confocal microscopy assays demonstrate that stitched peptides display superior cell penetrating ability compared to their stapled counterparts, suggesting that this technology may be useful not only in the context of enhancing the drug-like properties of α-helical peptides but also in producing potent agents for the intracellular delivery of proteins and oligonucleotides.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2014/jacsat.2014.136.issue-35/ja505141j/production/images/medium/ja-2014-05141j_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja505141j'>ACS Electronic Supporting Info</A></P>
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