State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
Biomaterials. 2013 Apr;34(13):3511-22. doi: 10.1016/j.biomaterials.2013.01.075. Epub 2013 Feb 13.
Recently, peptide drugs have evolved into mainstream therapeutics, representing a significant portion of the pharmaceutical market. However, their bioavailability remains to be improved compared with that of chemical drugs. Here, we screened and identified a new peptide, Ctry2459, from a scorpion venom peptide library that was proven to inhibit hepatitis C virus (HCV) infection via inactivating infectious viral particles. However, Ctry2459 cannot suppress established infection of HCV because of the poor cellular uptake and restriction of endosomes. Based on the molecular template of the Ctry2459 peptide, we designed two histidine-rich peptides (Ctry2459-H2 and Ctry2459-H3) with significantly enhanced cellular uptake and improved intracellular distribution. Moreover, the two mutated peptides, as well as the wild-type peptide Ctry2459, exhibited virucidal activities against HCV. In distinct contrast to the Ctry2459 peptide, the mutated peptides significantly suppressed the established HCV infection at the cellular level but demonstrated lower cytotoxic and hemolytic activities. Our work presents an effective design strategy for optimizing natural antiviral peptides and opens a new avenue for enhancing the bioavailability of peptide drugs.
最近，肽类药物已发展成为主流治疗药物，占据了相当大一部分的医药市场。然而，与化学药物相比，它们的生物利用度仍有待提高。在这里，我们从蝎毒肽文库中筛选并鉴定出一种新的肽 Ctry2459，该肽已被证明通过使感染性病毒颗粒失活来抑制丙型肝炎病毒（HCV）感染。然而，由于细胞摄取能力差和内体限制，Ctry2459 不能抑制已建立的 HCV 感染。基于 Ctry2459 肽的分子模板，我们设计了两种组氨酸丰富的肽（Ctry2459-H2 和 Ctry2459-H3），它们具有显著增强的细胞摄取能力和改善的细胞内分布。此外，这两种突变肽以及野生型肽 Ctry2459 均表现出抗 HCV 的病毒杀伤活性。与 Ctry2459 肽明显不同的是，突变肽在细胞水平上显著抑制已建立的 HCV 感染，但表现出较低的细胞毒性和溶血活性。我们的工作为优化天然抗病毒肽提供了一种有效的设计策略，并为提高肽类药物的生物利用度开辟了新途径。
