Development of Endocyclic Control Elements for Peptide Macrocycles

Solomon D. Appavoo, Takuya Kaji, John R. Frost, Conor C.G. Scully, Andrei K. Yudin

研究成果: Article査読

29 被引用数 (Scopus)

抄録

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α 4 β 7 integrin antagonist.

本文言語English
ページ(範囲)8763-8770
ページ数8
ジャーナルJournal of the American Chemical Society
140
28
DOI
出版ステータスPublished - 2018 7 18
外部発表はい

ASJC Scopus subject areas

  • 触媒
  • 化学 (全般)
  • 生化学
  • コロイド化学および表面化学

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