Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery
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 pept...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2025.1637329/full |
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| author | Yaqi Zhou Dongyuan Wang Jiean Xu Nan Zheng |
| author_facet | Yaqi Zhou Dongyuan Wang Jiean Xu Nan Zheng |
| author_sort | Yaqi Zhou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6a623d7943b34a8c99a09f003ae5f7c7 |
| institution | Matheson Library |
| issn | 2296-2646 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj-art-6a623d7943b34a8c99a09f003ae5f7c72025-06-27T05:31:30ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462025-06-011310.3389/fchem.2025.16373291637329Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discoveryYaqi Zhou0Dongyuan Wang1Jiean Xu2Nan Zheng3Department of Physiology and Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaDepartment of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Physiology and Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, ChinaTranslational Innovation Center, Shenzhen Bay Laboratory, Shenzhen, ChinaDisulfide 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.https://www.frontiersin.org/articles/10.3389/fchem.2025.1637329/fulldisulfide surrogatemethylene thioacetal bondstability and bioactivitypeptide drug discoverypeptide synthesis |
| spellingShingle | Yaqi Zhou Dongyuan Wang Jiean Xu Nan Zheng Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery Frontiers in Chemistry disulfide surrogate methylene thioacetal bond stability and bioactivity peptide drug discovery peptide synthesis |
| title | Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery |
| title_full | Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery |
| title_fullStr | Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery |
| title_full_unstemmed | Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery |
| title_short | Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery |
| title_sort | strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery |
| topic | disulfide surrogate methylene thioacetal bond stability and bioactivity peptide drug discovery peptide synthesis |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2025.1637329/full |
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