Rafferty John, Nagaraj Hema, McCloskey Alice P, Huwaitat Rawan, Porter Simon, Albadr Alyaa, Laverty Garry
Queen's University Belfast - School of Pharmacy, Belfast, United Kingdom.
Curr Med Chem. 2016;23(37):4231-4259. doi: 10.2174/0929867323666160909155222.
Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somatostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or monotherapy for prostate and breast cancer, and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutical industry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers.
肽作为临床治疗药物正越来越受到关注。这些高度可调节的分子可以进行定制，以实现理想的生物相容性和生物降解性，同时具有选择性和强效的治疗效果。尽管肽产品在扩大生产规模和获得许可方面存在挑战，但其巨大的临床潜力体现在已上市的60多种基于肽的治疗药物，以及目前处于研发阶段的另外500种衍生物中。肽已被证明对多种疾病状态有效，包括：2型糖尿病（使用已获许可的胰高血糖素样肽-1受体激动剂利拉鲁肽进行控制）；用利那洛肽治疗的肠易激综合征（目前处于审批阶段）；肢端肥大症（用八肽生长抑素类似物兰瑞肽和奥曲肽治疗）；选择性或广谱杀菌剂，如革兰氏阳性选择性PTP-7和抗真菌药helomicin；抗癌药物，包括用于前列腺癌和乳腺癌辅助治疗或单一疗法的戈舍瑞林，以及第一种上市的抗前列腺癌肽衍生疫苗sipuleucel-T。研究还集中在提高肽的生物稳定性上。这可以通过多种机制实现，包括用D-氨基酸形式取代天然存在的L-氨基酸对映体、脂化、肽模拟物、N-甲基化、环化以及利用载体系统。自组装肽的开发为缓释肽制剂铺平了道路，目前已有两个这样的获许可实例，即兰瑞肽和奥曲肽。基于肽的产品的多功能性和可调节性导致肽疗法的转化增加，然而，在更广泛的应用方面仍存在重大挑战。本综述重点介绍了迄今为止发现的一些著名的肽治疗药物，以及制药行业在将这些分子转化为临床应用以造福患者时遇到的困难，并为最具挑战性的障碍提供了一些可能的解决方案。
