Sala Valentina, Cnudde Sophie Julie, Murabito Alessandra, Massarotti Alberto, Hirsch Emilio, Ghigo Alessandra
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126, Torino, Italy.
Department of Pharmaceutical Science, University of Piemonte Orientale "A. Avogadro", Largo Donegani 2, 28100, Novara, Italy.
Eur J Med Chem. 2021 Mar 5;213:113191. doi: 10.1016/j.ejmech.2021.113191. Epub 2021 Jan 16.
Cystic fibrosis (CF) is the most common amongst rare genetic diseases, affecting more than 70.000 people worldwide. CF is characterized by a dysfunctional chloride channel, termed cystic fibrosis conductance regulator (CFTR), which leads to the production of a thick and viscous mucus layer that clogs the lungs of CF patients and traps pathogens, leading to chronic infections and inflammation and, ultimately, lung damage. In recent years, the use of peptides for the treatment of respiratory diseases, including CF, has gained growing interest. Therapeutic peptides for CF include antimicrobial peptides, inhibitors of proteases, and modulators of ion channels, among others. Peptides display unique features that make them appealing candidates for clinical translation, like specificity of action, high efficacy, and low toxicity. Nevertheless, the intrinsic properties of peptides, together with the need of delivering these compounds locally, e.g. by inhalation, raise a number of concerns in the development of peptide therapeutics for CF lung disease. In this review, we discuss the challenges related to the use of peptides for the treatment of CF lung disease through inhalation, which include retention within mucus, proteolysis, immunogenicity and aggregation. Strategies for overcoming major shortcomings of peptide therapeutics will be presented, together with recent developments in peptide design and optimization, including computational analysis and high-throughput screening.
囊性纤维化（CF）是最常见的罕见遗传病，全球有超过7万人受其影响。CF的特征是一种功能失调的氯离子通道，称为囊性纤维化跨膜传导调节因子（CFTR），这会导致产生一层浓稠的黏液，堵塞CF患者的肺部并困住病原体，引发慢性感染和炎症，最终导致肺损伤。近年来，使用肽来治疗包括CF在内的呼吸道疾病越来越受到关注。用于CF的治疗性肽包括抗菌肽、蛋白酶抑制剂和离子通道调节剂等。肽具有独特的特性，使其成为临床转化的有吸引力的候选物，如作用特异性、高效性和低毒性。然而，肽的固有特性，以及通过吸入等方式将这些化合物局部递送的需求，在CF肺部疾病肽治疗药物的开发中引发了一些问题。在这篇综述中，我们讨论了通过吸入使用肽治疗CF肺部疾病相关的挑战，包括在黏液中的滞留、蛋白水解、免疫原性和聚集。将介绍克服肽治疗药物主要缺点的策略，以及肽设计和优化的最新进展，包括计算分析和高通量筛选。
