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Design of thioether cyclic peptide scaffolds with passive permeability and oral exposure

Golosov, Andrei, Flyer, Alec, Amin, Jakal, Babu, Charles, Gampe, Christian, Li, Jingzhou, Liu, Eugene, Nakajima, Katsumasa, Nettleton, David, Patel, Tej, Reid, Patrick, Yang, Lihua and Monovich, Lauren (2021) Design of thioether cyclic peptide scaffolds with passive permeability and oral exposure. Journal of medicinal chemistry, 64 (5). pp. 2622-2633.


Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel, but independent tracks. Less precedence combines their respective attributes, in turn limiting potential to identify permeable peptide ligands for key protein targets. Herein, we present one strategy for focusing the powerful ligand-finding capability of DNA- or RNA-templated peptide synthesis within permeability-biased property space. Despite higher than standard molecular weights (from 774 to 1076 g·mol-1), the 6-, 7-, and 8-mer cyclic peptides of the present contribution are partially N-methylated to achieve low energy conformations with low desolvation penalties. The N-methylation patterns were selected using in silico methods, then experimentally validat-ed with high passive permeability and oral exposure. Further, the present work shows that chemical structures that overlap the synthetic capabilities of DNA- or RNA-templated peptide syntheses in water, can be both permeable and orally exposed. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward per-meability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased lig-ands to a variety of protein targets.

Item Type: Article
Keywords: oral, peptide, macrocycle
Date Deposited: 16 Jun 2021 00:45
Last Modified: 16 Jun 2021 00:45


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