Engineered carboxylesterase enzymes and methods for their use in macrocyclization of non-canonical tetrapeptides

Engineered carboxylesterases address the limitations of chemical and enzymatic methods by providing high-yield, regioselective macrocyclization of oligopeptides, particularly tetrapeptides, suitable for large-scale production of therapeutic peptides.

WO2026019621A1 Publication Date: 2026-01-22MERCK SHARP & DOHME LLC
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Patent Information

Application Number
PCT/US2025/037058
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2024-07-15
Filing Date
2025-07-10
Publication Date
2026-01-22

AI Technical Summary

Technical Problem

Existing methods for synthesizing macrocyclic peptides face challenges such as low specificity, formation of impurities and undesired byproducts, and inefficiencies in chemical approaches, while enzymatic methods struggle with scalability, robustness, and tolerance to process conditions.

Method used

Engineered carboxylesterases with improved activity, enantioselectivity, and reduced product hydrolysis are developed through directed evolution, enabling the biocatalytic synthesis of macrocyclic peptides with high yields and regioselectivity.

Benefits of technology

The engineered carboxylesterases achieve efficient macrocyclization of oligopeptides, including tetrapeptides with non-canonical amino acids, demonstrating enhanced activity, thermostability, and solvent tolerance, suitable for large-scale production of therapeutic peptides.

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Abstract

The present disclosure provides engineered carboxylesterase enzymes having improved activity in catalyzing cyclization of short polypeptides, as compared to a naturally occurring wild-type carboxylesterase enzyme. These variants catalyze the cyclization of linear tetrapeptides with high regioselectivity. Also provided are polynucleotides and expression vectors encoding the carboxylesterase enzymes and methods of using the carboxylesterase enzymes to generate cyclic tetrapeptides containing non-canonical amino acids.
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