Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, 5, Jalan Universiti, Bandar Sunway, Selangor, 47500, Malaysia.
Virology Unit, Infectious Disease Research Centre, Institute for Medical Research, National Institutes of Health, Setia Alam, Shah Alam, Selangor, Malaysia.
Virology. 2023 Mar;580:10-27. doi: 10.1016/j.virol.2023.01.016. Epub 2023 Jan 31.
Dengue infections pose a critical threat to public health worldwide. Since there are no clinically approved antiviral drugs to treat dengue infections caused by the four dengue virus (DENV) serotypes, there is an urgent need to develop effective antivirals. Peptides are promising antiviral candidates due to their specificity and non-toxic properties. The DENV envelope (E) protein was selected for the design of antiviral peptides due to its importance in receptor binding and viral fusion to the host cell membrane. Twelve novel peptides were designed to mimic regions containing critical amino acid residues of the DENV E protein required for interaction with the host. A total of four peptides were identified to exhibit potent inhibitory effects against at least three or all four DENV serotypes. Peptide 3 demonstrated all three modes of action: cell protection and inhibition of post-infection against all four DENV serotypes, whereas direct virus-inactivating effects were only observed against DENV-2, 3, and 4. Peptide 4 showed good direct virus-inactivating effects against DENV-2 (74.26%) as well as good inhibitions of DENV-1 (80.37%) and DENV-4 (72.22%) during the post-infection stage. Peptide 5 exhibited direct virus-inactivating effects against all four DENV serotypes, albeit at lower inhibition levels against DENV-1 and DENV-3. It also exhibited highly significant inhibition of DENV-4 (89.31%) during post-infection. Truncated peptide 5F which was derived from peptide 5 showed more significant inhibition of DENV-4 (91.58%) during post-infection and good direct virus-inactivating effects against DENV-2 (77.55%) at a lower concentration of 100 μM. Peptide 3 could be considered as the best antiviral candidate for pre- and post-infection treatments of DENV infections in regions with four circulating dengue serotypes. However, if the most predominant dengue serotype for a particular region could be identified, peptides with significantly high antiviral activities against that particular dengue serotype could serve as more suitable antiviral candidates. Thus, peptide 5F serves as a more suitable antiviral candidate for post-infection treatment against DENV-4.
登革热感染对全球公共卫生构成重大威胁。由于目前尚无临床批准的抗病毒药物可治疗由四种登革热病毒（DENV）血清型引起的登革热感染，因此迫切需要开发有效的抗病毒药物。由于其特异性和非毒性特性，肽类是很有前途的抗病毒候选物。由于 DENV 包膜（E）蛋白在与宿主细胞膜的受体结合和病毒融合中起重要作用，因此选择该蛋白设计抗病毒肽。设计了 12 种新型肽以模拟 DENV E 蛋白中与宿主相互作用所需的关键氨基酸残基的区域。总共鉴定出四种肽，它们对至少三种或所有四种 DENV 血清型均具有很强的抑制作用。肽 3 表现出三种作用方式：对所有四种 DENV 血清型均具有细胞保护和感染后抑制作用，而仅对 DENV-2、3 和 4 观察到直接的病毒失活作用。肽 4 对 DENV-2 具有良好的直接病毒失活作用（74.26％），以及在感染后阶段对 DENV-1（80.37％）和 DENV-4（72.22％）的良好抑制作用。肽 5 对所有四种 DENV 血清型均具有直接的病毒失活作用，尽管对 DENV-1 和 DENV-3 的抑制作用较低。它在感染后阶段对 DENV-4 也表现出高度显著的抑制作用（89.31％）。源自肽 5 的截短肽 5F 在感染后对 DENV-4 的抑制作用更为显著（91.58％），并且在浓度较低的 100μM 时对 DENV-2 具有良好的直接病毒失活作用。肽 3 可被视为在具有四种循环登革热血清型的地区进行 DENV 感染的预感染和感染后治疗的最佳抗病毒候选物。但是，如果可以确定特定地区最主要的登革热血清型，则针对该特定登革热血清型具有明显高抗病毒活性的肽可以作为更合适的抗病毒候选物。因此，肽 5F 是针对 DENV-4 感染后治疗的更合适的抗病毒候选物。
