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Volume 14
Issue 8
10.3390/antibiotics14080784
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Article

Rational Engineering of a Brevinin-2 Peptide: Decoupling Potency from Toxicity Through C-Terminal Truncation and N-Terminal Chiral Substitution

by
Aifang Yao
1,*,†,
Zeyu Zhang
2,†,
Zhengmin Song
3,
Yi Yuan
1,*,
Xiaoling Chen
3,*,
Chengbang Ma
3,
Tianbao Chen
3,
Chris Shaw
3,
Mei Zhou
3 and
Lei Wang
3
1
College of Biological Science and Engineering, Fuzhou University, Fuzhou 350108, China
2
Engineering and Technology Institute Groningen, Faculty of Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
3
School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Antibiotics 2025, 14(8), 784; https://doi.org/10.3390/antibiotics14080784 (registering DOI)
Submission received: 27 June 2025 / Revised: 27 July 2025 / Accepted: 31 July 2025 / Published: 1 August 2025
(This article belongs to the Section Antimicrobial Peptides)
Versions Notes

Abstract

Background/Objectives: The clinical potential of antimicrobial peptides (AMPs) against dual threats like antimicrobial resistance (AMR) and cancer is often limited by their high host cell toxicity. Here, we focused on brevinin-2OS (B2OS), a novel peptide from the skin of Odorrana schmackeri with potent haemolytic activity. The objective was to study the structure–activity relationship and optimise the safety via targeted modifications. Methods: A dual-modification strategy involving C-terminal truncation and subsequent N-terminal D-amino acid substitution was employed. The bioactivities and safety profiles of the resulting analogues were evaluated using antimicrobial, haemolysis, and cytotoxicity assays. Result: Removal of the rana box in B2OS(1-22)-NH2 substantially reduced haemolysis while maintaining bioactivities. Remarkably, the D-leucine substitution in [D-Leu2]B2OS(1-22)-NH2 displayed a superior HC50 value of 118.1 µM, representing a more than ten-fold improvement compared to its parent peptide (HC50 of 10.44 µM). This optimised analogue also demonstrated faster bactericidal kinetics and enhanced membrane permeabilisation, leading to a greater than 22-fold improvement in its therapeutic index against Gram-positive bacteria. Conclusions: The C-terminal rana box is a primary determinant of toxicity rather than a requirement for activity in the B2OS scaffold. The engineered peptide [D-Leu2]B2OS(1-22)-NH2 emerges as a promising lead compound, and this dual-modification strategy provides a powerful design principle for developing safer, more effective peptide-based therapeutics.
Keywords: antimicrobial peptide; brevinin-2; peptide modification; structure–activity relationship; therapeutic index antimicrobial peptide; brevinin-2; peptide modification; structure–activity relationship; therapeutic index

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MDPI and ACS Style

Yao, A.; Zhang, Z.; Song, Z.; Yuan, Y.; Chen, X.; Ma, C.; Chen, T.; Shaw, C.; Zhou, M.; Wang, L. Rational Engineering of a Brevinin-2 Peptide: Decoupling Potency from Toxicity Through C-Terminal Truncation and N-Terminal Chiral Substitution. Antibiotics 2025, 14, 784. https://doi.org/10.3390/antibiotics14080784

AMA Style

Yao A, Zhang Z, Song Z, Yuan Y, Chen X, Ma C, Chen T, Shaw C, Zhou M, Wang L. Rational Engineering of a Brevinin-2 Peptide: Decoupling Potency from Toxicity Through C-Terminal Truncation and N-Terminal Chiral Substitution. Antibiotics. 2025; 14(8):784. https://doi.org/10.3390/antibiotics14080784

Chicago/Turabian Style

Yao, Aifang, Zeyu Zhang, Zhengmin Song, Yi Yuan, Xiaoling Chen, Chengbang Ma, Tianbao Chen, Chris Shaw, Mei Zhou, and Lei Wang. 2025. "Rational Engineering of a Brevinin-2 Peptide: Decoupling Potency from Toxicity Through C-Terminal Truncation and N-Terminal Chiral Substitution" Antibiotics 14, no. 8: 784. https://doi.org/10.3390/antibiotics14080784

APA Style

Yao, A., Zhang, Z., Song, Z., Yuan, Y., Chen, X., Ma, C., Chen, T., Shaw, C., Zhou, M., & Wang, L. (2025). Rational Engineering of a Brevinin-2 Peptide: Decoupling Potency from Toxicity Through C-Terminal Truncation and N-Terminal Chiral Substitution. Antibiotics, 14(8), 784. https://doi.org/10.3390/antibiotics14080784

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