Laboratory affiliated to Pasteur Italia-Fondazione Cenci Bolognetti, Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
Center for Life Nano Science@ Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.
Curr Med Chem. 2020;27(9):1405-1419. doi: 10.2174/0929867326666190722095408.
Antimicrobial Peptides (AMPs) are the key effectors of the innate immunity and represent promising molecules for the development of new antibacterial drugs. However, to achieve this goal, some problems need to be overcome: (i) the cytotoxic effects at high concentrations; (ii) the poor biostability and (iii) the difficulty in reaching the target site. Frog skin is one of the richest natural storehouses of AMPs, and over the years, many peptides have been isolated from it, characterized and classified into several families encompassing temporins, brevinins, nigrocins and esculentins. In this review, we summarized how the isolation/characterization of peptides belonging to the esculentin-1 family drove us to the design of an analogue, i.e. esculentin-1a(1-21)NH2, with a powerful antimicrobial action and immunomodulatory properties. The peptide had a wide spectrum of activity, especially against the opportunistic Gram-negative bacterium Pseudomonas aeruginosa. We described the structural features and the in vitro/in vivo biological characterization of this peptide as well as the strategies used to improve its biological properties. Among them: (i) the design of a diastereomer carrying Damino acids in order to reduce the peptide's cytotoxicity and improve its half-life; (ii) the covalent conjugation of the peptide to gold nanoparticles or its encapsulation into poly(lactide- co-glycolide) nanoparticles; and (iii) the peptide immobilization to biomedical devices (such as silicon hydrogel contact lenses) to obtain an antibacterial surface able to reduce microbial growth and attachment. Summing up the best results obtained so far, this review traces all the steps that led these frog-skin AMPs to the direction of peptide-based drugs for clinical use.
抗菌肽 (AMPs) 是先天免疫的关键效应物，是开发新型抗菌药物的有前途的分子。然而，要实现这一目标，需要克服一些问题：(i) 高浓度时的细胞毒性作用；(ii) 较差的生物稳定性；(iii) 难以到达靶位。青蛙皮肤是 AMPs 的天然宝库之一，多年来，从它中分离出许多肽，并对其进行了表征和分类，归入几大家族，包括 temporins、brevinins、nigrocins 和 esculentins。在这篇综述中，我们总结了属于 esculentin-1 家族的肽的分离/表征如何促使我们设计一种类似物，即 esculentin-1a(1-21)NH2，它具有强大的抗菌作用和免疫调节特性。该肽具有广泛的活性，特别是对机会性革兰氏阴性菌铜绿假单胞菌。我们描述了这种肽的结构特征和体外/体内生物学特性以及用于改善其生物学特性的策略。其中包括：(i) 设计带有 Damino 氨基酸的非对映异构体，以降低肽的细胞毒性并提高其半衰期；(ii) 将肽共价偶联到金纳米粒子或将其包封到聚 (乳酸-共-乙醇酸) 纳米粒子中；(iii) 将肽固定到生物医学设备（如硅水凝胶隐形眼镜）上，以获得能够减少微生物生长和附着的抗菌表面。总结迄今为止取得的最佳结果，本文综述追溯了这些源自青蛙皮肤的 AMPs 走向临床应用的肽类药物的所有步骤。
