Voronko Olga Evgenevna, Khotina Victoria Alexandrovna, Kashirskikh Dmitry Alexandrovich, Lee Arthur Anatolievich, Gasanov Vagif Ali Oglu
Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia.
Int J Mol Sci. 2025 Aug 21;26(16):8103. doi: 10.3390/ijms26168103.
Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is hindered by several limitations, including low proteolytic stability, cytotoxicity, and high production costs. To overcome these challenges, a wide range of design strategies have been employed to modify LL-37 and improve its therapeutic potential. LL-37-based analogs represent promising candidates for the development of next-generation antimicrobial and immunomodulatory therapies. Despite significant progress, further research is required to optimize peptide design, ensure cost-effective production, and validate long-term safety and efficacy. Advances in computational modeling, high-throughput screening, and nanotechnology will play an important role in the translation of modified cathelicidins into clinical practice. This review summarizes key strategies of chemical and structural modifications of LL-37 aimed at enhancing its functional properties. Particular attention is given to truncated and retro-analogs, which preserve or improve biological activity while exhibiting reduced toxicity and increased proteolytic resistance. Furthermore, we highlight the use of nanoscale delivery systems, which facilitate targeted delivery, prolong peptide half-life, and mitigate cytotoxic effects.
cathelicidin是一类具有广谱活性和免疫调节功能的抗菌肽（AMPs）。其中，唯一的人类cathelicidin LL-37因其强大的抗菌、抗病毒、抗真菌、抗寄生虫和抗肿瘤特性而备受关注。然而，LL-37的临床应用受到多种限制，包括蛋白水解稳定性低、细胞毒性和生产成本高。为了克服这些挑战，人们采用了多种设计策略来修饰LL-37并提高其治疗潜力。基于LL-37的类似物是开发下一代抗菌和免疫调节疗法的有希望的候选物。尽管取得了重大进展，但仍需要进一步研究来优化肽设计、确保具有成本效益的生产并验证长期安全性和有效性。计算建模、高通量筛选和纳米技术的进展将在将修饰的cathelicidin转化为临床实践中发挥重要作用。本综述总结了旨在增强LL-37功能特性的化学和结构修饰的关键策略。特别关注截短和反向类似物，它们保留或改善了生物活性，同时表现出降低的毒性和增加的蛋白水解抗性。此外，我们强调了纳米级递送系统的使用，该系统有助于靶向递送、延长肽的半衰期并减轻细胞毒性作用。
