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Pharmaceutics
Volume 18
Issue 7
10.3390/pharmaceutics18070840
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Multidimensional Modification and Functional Optimization of Melittin: From Natural Toxic Peptide to Safe and Effective Therapeutics

by
Zhengyu Chen
1,†,
Chunli Su
2,†,
Tianyao Guo
1,
Zhiting Fang
1,
Yujie Peng
3,
Xiantao Yang
1,* and
Hongli Liao
1,*
1
School of Pharmacy, Chengdu Medical College, 783, Xindu Avenue, Xindu District, Chengdu 610500, China
2
School of Public Health, Chengdu Medical College, 783 Xindu Avenue, Xindu District, Chengdu 610500, China
3
Yibin Center for Disease Control and Prevention, Yibin 644600, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceutics 2026, 18(7), 840; https://doi.org/10.3390/pharmaceutics18070840
Submission received: 15 May 2026 / Revised: 25 June 2026 / Accepted: 7 July 2026 / Published: 9 July 2026
(This article belongs to the Section Drug Targeting and Design)
Versions Notes

Abstract

Melittin, a cationic amphipathic 26-residue peptide from bee venom, displays broad-spectrum antibacterial, antitumor and anti-inflammatory activities, yet severe hemolysis, poor cell selectivity, rapid plasma degradation and high immunogenicity hinder its clinical translation. Structural modification is a vital strategy to overcome its druggability limitations. This review systematically summarizes three mainstream modification approaches of melittin: sequence remodeling, chemical derivatization and conjugate engineering. We illustrate how these strategies tune melittin’s conformation, charge and amphiphilicity to lower toxicity and immunogenicity, improve in vivo stability, and enable targeted stimulus-responsive delivery, while unraveling its core functional sites and mechanisms. Current research gaps and future directions including combined modification, multifunctional intelligent conjugates, preclinical safety assessment and scaled production optimization are discussed, providing theoretical support for developing safe, effective melittin-based therapeutics.
Keywords: melittin; peptide; structural modification melittin; peptide; structural modification

Share and Cite

MDPI and ACS Style

Chen, Z.; Su, C.; Guo, T.; Fang, Z.; Peng, Y.; Yang, X.; Liao, H. Multidimensional Modification and Functional Optimization of Melittin: From Natural Toxic Peptide to Safe and Effective Therapeutics. Pharmaceutics 2026, 18, 840. https://doi.org/10.3390/pharmaceutics18070840

AMA Style

Chen Z, Su C, Guo T, Fang Z, Peng Y, Yang X, Liao H. Multidimensional Modification and Functional Optimization of Melittin: From Natural Toxic Peptide to Safe and Effective Therapeutics. Pharmaceutics. 2026; 18(7):840. https://doi.org/10.3390/pharmaceutics18070840

Chicago/Turabian Style

Chen, Zhengyu, Chunli Su, Tianyao Guo, Zhiting Fang, Yujie Peng, Xiantao Yang, and Hongli Liao. 2026. "Multidimensional Modification and Functional Optimization of Melittin: From Natural Toxic Peptide to Safe and Effective Therapeutics" Pharmaceutics 18, no. 7: 840. https://doi.org/10.3390/pharmaceutics18070840

APA Style

Chen, Z., Su, C., Guo, T., Fang, Z., Peng, Y., Yang, X., & Liao, H. (2026). Multidimensional Modification and Functional Optimization of Melittin: From Natural Toxic Peptide to Safe and Effective Therapeutics. Pharmaceutics, 18(7), 840. https://doi.org/10.3390/pharmaceutics18070840

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