Improve the Stability and Activity of Antimicrobial Peptides by the Proline-Based PXXP Hinge Structure
Developing a simple and effective strategy to enhance the stability of antimicrobial peptides (AMPs) is critical for successful AMP design. In this study, we leveraged the property of proline to form hinge-like structures and designed a series of repetitive symmetrical sequence AMPs with different proline-based hinge centers (PWWP, PKKP, and PWKP), proposing a template of (KW)<i><sub>n</sub></i>PXXP(WK)<i><sub>n</sub></i>-NH<sub>2</sub> (where XX = WW, <i>n</i> = 1-4 or XX = KK, WK, <i>n</i> = 2-4). The corresponding templates without hinge structures, (KW)<i><sub>n</sub></i>(WK)<i><sub>n</sub></i>-NH<sub>2</sub> (<i>n</i> = 1-4), were used as controls. Through comprehensive evaluations of activity, toxicity, and stability, we identified two promising AMP candidates, (KW)<sub>3</sub>PK and (KW)<sub>3</sub>PWK, which demonstrated excellent antibacterial activity, cell selectivity, and stability. Our findings indicate that incorporating a proline-containing PXXP hinge structure into AMP sequences could serve as an effective strategy to enhance AMP stability.
Authors
- Zufang Ba
- Pengyi Yan (ORCID: https://orcid.org/0000-0002-4038-3283)
- Bingqian Ren
- Tingting Yang (ORCID: https://orcid.org/0000-0001-9927-3057)
- Sanhu Gou (ORCID: https://orcid.org/0000-0003-3231-7427)
- Jingman Ni (ORCID: https://orcid.org/0000-0002-8728-1268)
- Xu Ouyang
- Yun Zhang (ORCID: https://orcid.org/0000-0002-4262-5354)
- Yu Wang (ORCID: https://orcid.org/0000-0002-8098-2491)
- Beibei Li (ORCID: https://orcid.org/0000-0001-9857-1263)
- Yao Liu (ORCID: https://orcid.org/0000-0001-6750-9950)
- Chao Zhong (ORCID: https://orcid.org/0000-0001-5975-9925)
- Hui Liu (ORCID: https://orcid.org/0000-0002-4077-6829)
- Yuhuan Zhao (ORCID: https://orcid.org/0000-0003-4190-624X)
- Zhongwei Yu (ORCID: https://orcid.org/0000-0002-8152-0889)
Institutions
- Macau University of Science and Technology (MO)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00364
- Citations
- 2
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 2.37
Funders
- Lanzhou University
- National Natural Science Foundation of China
- Chinese Academy of Medical Sciences
- Program for Changjiang Scholars and Innovative Research Team in University