Peptides as Therapeutic Agents for Dengue Virus

Chew, Miaw-Fang; Poh, Keat-Seong; Poh, Chit-Laa

On the other hand, Behnam et al. (2015) utilized the Bz-Arg-Lys-Nle as the core sequence to further optimize the chemical structure to improve its antiviral potential against the NS2B-NS3 protease [169] . Tripeptide hybrid 83 was created by the combination of 4-CF3-benzyl ether and the thiazole cap, while tripeptide hybrid 86 was created by the combination of 4-CF3-benzyl ether and the thien-2-yl cap. Both of the peptide hybrids successfully showed improved Ki values of 12 nM and 19 nM, respectively. Thus far, these are the two peptide hybrids which possess the highest binding affinity against the NS2B-NS3 protease. Nonetheless, the derivative 83 which possessed the highest binding affinity had a lower EC50 value of 20 µM in reducing the virus titer as compared to the derivative 86 (EC50 value of 7 µM) while the derivative 104 and derivative 90 were found to have the most potent EC50 value of 3.42 µM and 4.06 µM, respectively. Theoretically, the inhibitor which has a higher binding affinity against a target would result in a higher antiviral property. But in contrast to the direct in vitro protein-peptide interaction assay, cellular antiviral assay in the cell culture is complicated by factors such as membrane permeability and metabolic stability. Data suggested that the lipophilicity of the tripeptide hybrids correlated well with the observed cellular antiviral activities which might be influenced by the fact that higher polarity (lower lipophilicity) could lead to weaker membrane permeability [169] . In this case, the tripeptide hybrid 104 was shown to be more lipophilic than the tripeptide hybrid 83. Moreover, data also indicated that the tripeptide hybrid 104 possessed a much higher half-life of 175 minutes compared to the tripeptide hybrid 83 (half-life of 45 minutes) in metabolic clearance via rat liver microsomes. These observations might offer the possible explanation of the higher antiviral activity of the tripeptide hybrid 104 in cellular assays as compared to the analogue of tripeptide hybrid 83 which possessed higher binding ability against DENV-2 protease in vitro.