The Influence of Disulfide, Thioacetal and Lanthionine-Bridges on the Conformation of a Macrocyclic Peptide.

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Darling WTP, Wieske LHE, Cook DT, Aliev AE, Caron L, Humphrys EJ, Figueiredo AM, Hansen DF, Erdélyi M, Tabor AB

Chemistry 30 (50) e202401654 [2024-09-05; online 2024-08-20]

Cyclisation of peptides by forming thioether (lanthionine), disulfide (cystine) or methylene thioacetal bridges between side chains is established as an important tool to stabilise a given structure, enhance metabolic stability and optimise both potency and selectivity. However, a systematic comparative study of the effects of differing bridging modalities on peptide conformation has not previously been carried out. In this paper, we have used the NMR deconvolution algorithm, NAMFIS, to determine the conformational ensembles, in aqueous solution, of three cyclic analogues of angiotensin(1-7), incorporating either disulfide, or non-reducible thioether or methylene thioacetal bridges. We demonstrate that the major solution conformations are conserved between the different bridged peptides, but the distribution of conformations differs appreciably. This suggests that subtle differences in ring size and bridging structure can be exploited to fine-tune the conformational properties of cyclic peptides, which may modulate their bioactivities.

Swedish NMR Centre (SNC) [Service]

PubMed 38953277

DOI 10.1002/chem.202401654

Crossref 10.1002/chem.202401654