Production of constrained L-cyclo-tetrapeptides by epimerization-resistant direct aminolysis

Huan Chen, Yuchen Zhang, Yuming Wen, Xinhao Fan, Nicholas Sciolino, Yanyun Lin, Leonard Breindel, Yuanwei Dai, Alexander Shekhtman (), Xiao-Song Xue () and Qiang Zhang ()
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Huan Chen: State University of New York, University at Albany
Yuchen Zhang: Chinese Academy of Sciences
Yuming Wen: State University of New York, University at Albany
Xinhao Fan: State University of New York, University at Albany
Nicholas Sciolino: State University of New York, University at Albany
Yanyun Lin: State University of New York, University at Albany
Leonard Breindel: State University of New York, University at Albany
Yuanwei Dai: State University of New York, University at Albany
Alexander Shekhtman: State University of New York, University at Albany
Xiao-Song Xue: Chinese Academy of Sciences
Qiang Zhang: State University of New York, University at Albany

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract The synthesis of constrained 12-membered rings is notably difficult. The main challenges result from constraints during the linear peptide cyclization. Attempts to overcome constraints through excessive activation frequently cause peptidyl epimerization, while insufficient activation of the C-terminus hampers cyclization and promotes intermolecular oligomer formation. We present a β-thiolactone framework that enables the synthesis of cyclo-tetrapeptides via direct aminolysis. This tactic utilizes a mechanism that restricts C-terminal carbonyl rotation while maintaining high reactivity, thereby enabling efficient head-to-tail amidation, reducing oligomerization, and preventing epimerization. A broad range of challenging cyclo-tetrapeptides ( > 20 examples) are synthesized in buffer and exhibits excellent tolerance toward nearly all proteinogenic amino acids. Previously unattainable macrocycles, such as cyclo-L-(Pro-Tyr-Pro-Val), have been produced and identified as μ-opioid receptor (MOR) agonists, with an EC50 value of 2.5 nM. Non-epimerizable direct aminolysis offers a practical solution for constrained peptide cyclization, and the discovery of MOR agonist activity highlights the importance of overcoming synthetic challenges for therapeutic development.

Date: 2024
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DOI: 10.1038/s41467-024-49329-3

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