Development of Endocyclic Control Elements for Peptide Macrocycles

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

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8763-8770
Number of pages8
JournalJournal of the American Chemical Society
Volume140
Issue number28
DOIs
Publication statusPublished - 2018 Jul 18
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint

Dive into the research topics of 'Development of Endocyclic Control Elements for Peptide Macrocycles'. Together they form a unique fingerprint.

Cite this