Efficient synthesis, stability-guided optimization and anti-ulcerative colitis evaluation of bee venom peptide melittin.

IF 2.2 4区 医学 Q3 CHEMISTRY, MEDICINAL
Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-12-01 Epub Date: 2025-08-07 DOI:10.1016/j.bmcl.2025.130357
Cheng-Jian Pang, Jing-Fang Yao, Qiu-Lan Lv, Li-Ze Zhang, Qian-Yao Yu, Li Zeng, Yun-Kun Qi
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Abstract

Ulcerative colitis (UC) is considered as one of the most prevalent inflammatory bowel diseases (IBDs), which increases risks for colectomy and colorectal cancer. However, due to moderate efficiency and potential side effects of first-line drugs, it is desirable to develop more efficient anti-UC agents. The natural peptide Melittin, which is the main active ingredient of bee venom, is considered as a potential scaffold for the development of anti-UC drugs. Nevertheless, as a linear amphipathic peptide, Melittin could be degraded by various proteases, suffering from poor stability and short half-lives. Previous studies on structural optimization or the potential of Melittin-derived peptides for anti-UC applications still remain limited. In this study, the stability-guided optimization and anti-UC evaluation were conducted on Melittin. The robust synthetic strategy, in vivo anti-UC activity, and anti-inflammatory mechanism were investigated. Compared with Melittin, the derived peptides represented by PCJ-675 were found to exhibit improved proteolytic stability. In the dextran sulfate sodium (DSS)-induced UC mice model, PCJ-675 could significantly alleviate both colon shortening and suppress inflammation symptoms in colon tissue. The western blotting and biochemical indicators suggested that the oral administration of PCJ-675 could protect the colon in colitis mice by inhibiting both the excessive activation of the inflammation-related TLR4/NF-κB pathway and the overexpression of pro-inflammatory cytokines (eg, IL-1β, IL-6, and TNF-α). Collectively, this study not only stablished robust strategies to improve the stability and anti-UC potential of Melittin, but also provided valuable references for the future development of natural cytotoxic peptides based anti-UC agents.

蜂毒肽蜂毒素的高效合成、稳定性优化及抗溃疡性结肠炎评价。
溃疡性结肠炎(UC)被认为是最常见的炎症性肠病(IBDs)之一,它增加了结肠切除术和结直肠癌的风险。然而,由于一线药物的疗效一般和潜在的副作用,需要开发更有效的抗uc药物。蜂毒的主要活性成分是天然多肽蜂毒素,被认为是开发抗uc药物的潜在支架。然而,作为一种线性两亲肽,Melittin可被多种蛋白酶降解,稳定性差,半衰期短。先前关于蜂毒肽衍生肽的结构优化或抗uc应用潜力的研究仍然有限。本研究对Melittin进行了稳定性导向优化和抗uc评价。研究了其强大的合成策略、体内抗uc活性和抗炎机制。与Melittin相比,以PCJ-675为代表的衍生肽具有更好的蛋白水解稳定性。在葡聚糖硫酸钠(dextran sulfate sodium, DSS)诱导的UC小鼠模型中,PCJ-675能显著缓解结肠缩短和抑制结肠组织炎症症状。western blotting及生化指标显示,口服PCJ-675可通过抑制炎症相关的TLR4/NF-κB通路的过度激活和促炎细胞因子(如IL-1β、IL-6、TNF-α)的过度表达来保护结肠炎小鼠结肠。综上所述,本研究不仅为提高Melittin的稳定性和抗uc潜力建立了稳健的策略,也为未来开发基于天然细胞毒肽的抗uc药物提供了有价值的参考。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.70
自引率
3.70%
发文量
463
审稿时长
27 days
期刊介绍: Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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