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Review
. 2025 Jun 27:13:1637329.
doi: 10.3389/fchem.2025.1637329. eCollection 2025.

Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery

Yaqi Zhou #  1 , Dongyuan Wang #  2 , Jiean Xu  1 , Nan Zheng  3
Affiliations
Review

Strategic applications of methylene thioacetal bonds as disulfide surrogates in peptide drug discovery

Yaqi Zhou et al. Front Chem. .

Abstract

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; peptide drug discovery; peptide synthesis; stability and bioactivity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(a) Representative bioactive disulfide-containing peptides. The peptide backbones were represented in cartoon colored in grey and disulfide bonds were represented in stick colored in yellow. Structures generated from PDBs (insulin 1EVR; salmon Calcitonin 7TYN; endothelin1 8XVH; human growth factor 1HGU; ziconotide 7MIX; ProTx2 6N4R; Cycloviolacin O14 2GJ0; S597 8DTL. (b) The development of disulfide bond surrogates and (c) their application in disulfide-rich peptide compounds, exemplified by conotoxins.
FIGURE 2
FIGURE 2
(a) Converting native disulfide into methylene thioacetal linkage by inserting the minimal “one-carbon” unit; Strategic applications of methylene thioacetal bonds as disulfide surrogates in bioactive peptides: (b) oxytocin; (c) conotoxin RgIA; (d) insulin; (e) BPTI; (f) human amylin; (g) human endothelin 1; (h) KRAS inhibitor; (i) interleukin 2 (j) HIV inhibitor.
See this image and copyright information in PMC

References

    1. Akondi K. B., Muttenthaler M., Dutertre S., Kaas Q., Craik D. J., Lewis R. J., et al. (2014). Discovery, synthesis, and structure-activity relationships of conotoxins. Chem. Rev. 114 (11), 5815–5847. 10.1021/cr400401e - DOI - PMC - PubMed
    1. Al Musaimi O., Lombardi L., Williams D. R., Albericio F. (2022). Strategies for improving peptide stability and delivery. Pharm. (Basel) 15 (10), 1283. 10.3390/ph15101283 - DOI - PMC - PubMed
    1. Anand U., Bandyopadhyay A., Jha N. K., Perez de la Lastra J. M., Dey A. (2023). Translational aspect in peptide drug discovery and development: an emerging therapeutic candidate. Biofactors 49 (2), 251–269. 10.1002/biof.1913 - DOI - PubMed
    1. Angell Y. L., Burgess K. (2007). Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions. Chem. Soc. Rev. 36 (10), 1674–1689. 10.1039/b701444a - DOI - PubMed
    1. Arai K., Okumura M., Lee Y. H., Katayama H., Mizutani K., Lin Y., et al. (2023). Diselenide-bond replacement of the external disulfide bond of insulin increases its oligomerization leading to sustained activity. Commun. Chem. 6 (1), 258. 10.1038/s42004-023-01056-4 - DOI - PMC - PubMed

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