MINI REVIEW article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 13 - 2025 | doi: 10.3389/fchem.2025.1637329
Strategic Applications of Methylene Thioacetal Bonds as Disulfide Surrogates in Peptide Drug Discovery
Provisionally accepted
- 1Guangzhou University of Chinese Medicine, Guangzhou, China
- 2Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, China
- 3Shenzhen Bay Laboratory, Shenzhen, China
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Disulfide bonds are indispensable structural motifs in bioactive peptides, stabilizing conformations which are critical for molecular recognition and biological activity. However, their intrinsic chemical lability under physiological and manufacturing conditions has long presented challenges in peptide drug development. Efforts to address these limitations have yielded a diverse array of disulfide bond surrogates, each with distinct advantages and constraints. Among these, methylene thioacetal linkages have recently emerged as a particularly promising method offering a favorable balance of structural fidelity, synthetic accessibility, and chemical stability. This review summarizes the biological importance and limitations of native disulfide bonds, surveys established strategies for disulfide bond mimicry, and provide a comprehensive summary of research leveraging methylene thioacetal chemistry as an emerging tool in the design of next-generation peptide therapeutics.
Keywords: disulfide surrogate, methylene thioacetal bond, stability and bioactivity, peptide drug discovery, peptide synthesis
Received: 29 May 2025; Accepted: 20 Jun 2025.
Copyright: © 2025 Zhou, Wang, Xu and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Nan Zheng, Shenzhen Bay Laboratory, Shenzhen, China
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