Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Adv Exp Med Biol. 2019;1117:215-240. doi: 10.1007/978-981-13-3588-4_12.
The incorporation of the innate immune system into humans is essential for survival and health due to the rapid replication of invading microbes and the delayed action of the adaptive immune system. Antimicrobial peptides are important components of human innate immunity. Over 100 such peptides have been identified in various human tissues. Human cathelicidin LL-37 is best studied, and there has been a growing interest in designing new peptides based on LL-37. This chapter describes the alternative processing of the human cathelicidin precursor, protease digestion, and lab cutting of LL-37. Both a synthetic peptide library and structure-based design are utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region. The minimal region of LL-37 can be function-dependent. We discuss the design and potential applications of LL-37 into antibacterial, antibiofilm, antiviral, antifungal, immune modulating, and anticancer peptides. LL-37 has been engineered into 17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. Both 17BIPHE2 and SAAP-148 can eliminate the ESKAPE pathogens and show topical in vivo antibiofilm efficacy. Also discussed are other application strategies, including peptide formulation, antimicrobial implants, and peptide-inducing factors such as vitamin D and sunlight. Finally, we summarize what we learned from peptide design based on human LL-37.
由于入侵微生物的快速复制和适应性免疫系统的延迟作用，人体先天免疫系统的融入对于生存和健康至关重要。抗菌肽是人体先天免疫系统的重要组成部分。在各种人体组织中已经鉴定出超过 100 种此类肽。人类防御素 LL-37 研究得最为透彻，人们越来越有兴趣基于 LL-37 设计新的肽。本章描述了人类防御素前体的替代加工、蛋白酶消化和 LL-37 的实验室切割。既利用了合成肽文库，也利用了基于结构的设计来识别活性区域。尽管具有挑战性，但确定 LL-37 的 3D 结构使得能够识别核心抗菌区域。LL-37 的最小区域可能是功能依赖性的。我们讨论了将 LL-37 设计成具有抗菌、抗生物膜、抗病毒、抗真菌、免疫调节和抗癌作用的肽的应用。LL-37 已被设计成 17BIPHE2，这是一种稳定、选择性和有效的抗菌、抗生物膜和抗癌肽。17BIPHE2 和 SAAP-148 都可以消除 ESKAPE 病原体，并显示出局部体内抗生物膜功效。还讨论了其他应用策略，包括肽制剂、抗菌植入物以及维生素 D 和阳光等肽诱导因子。最后，我们总结了从基于人类 LL-37 的肽设计中获得的经验教训。
