Design of histidine-rich peptides with enhanced bioavailability and inhibitory activity against hepatitis C virus.
Design of histidine-rich peptides with enhanced bioavailability and inhibitory activity against hepatitis C virus.
复制标题
设计富含组氨酸的肽，具有增强的生物利用度和对丙型肝炎病毒的抑制活性。
DOI：
10.1016/j.biomaterials.2013.01.075
复制
发表时间：
2013-04
期刊：
影响因子：
14
通讯作者：
Cao Z
中科院分区：
文献类型：
--
作者：
Hong W;Zhang R;Di Z;He Y;Zhao Z;Hu J;Wu Y;Li W;Cao Z
最近，肽类药物已发展成为主流治疗药物，占医药市场的很大一部分。但与化学药物相比，其生物利用度仍有待提高。在这里，我们筛选并确定了一个新的肽，Ctry 2459，从蝎毒肽库，被证明是通过灭活感染性病毒颗粒抑制丙型肝炎病毒（HCV）感染。然而，Ctry 2459不能抑制已建立的HCV感染，因为差的细胞摄取和内体的限制。基于Ctry 2459肽的分子模板，我们设计了两个富含组氨酸的肽（Ctry 2459-H2和Ctry 2459-H3），其具有显著增强的细胞摄取和改善的细胞内分布。此外，两个突变的肽，以及野生型肽Ctry 2459，表现出对HCV的杀病毒活性。与Ctry 2459肽形成鲜明对比，突变肽在细胞水平上显著抑制了已建立的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，为提高肽类药物的生物利用度开辟了一条新的途径。
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.
登录
查看更多内容
影响因子：
7.3
作者：
Heitz F;Morris MC;Divita G
通讯作者：
Divita G
影响因子：
3.7
作者：
Langlet-Bertin, Berangere;Leborgne, Christian;Kichler, Antoine
通讯作者：
Kichler, Antoine
影响因子：
--
作者：
Shiraishi, T;Pankratova, S;Nielsen, PE
通讯作者：
Nielsen, PE
影响因子：
4.1
作者：
Bartz, Rene;Fan, Haihong;Barnett, Stanley F.
通讯作者：
Barnett, Stanley F.
影响因子：
6.4
作者：
Eron, JJ;Gulick, RM;Miralles, GD
通讯作者：
Miralles, GD