Peptides as Therapeutic Agents for Dengue Virus

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

NS5 is a large multifunctional protein which plays an important role in viral replication and modulation of the host immune response. It contains RNA-dependent RNA polymerase domain at the C-terminal end which is essential for viral replication and methyltransferase at the N-terminal region for RNA capping [155, 179] . These functions are essential for viral replication, thereby making NS5 a promising target for antiviral drug development. Inhibiting the polymerase or methyltransferase function can actively suppress virus growth and propagation in host cells [180] . Both NITD-008 and Balapiravir are examples of nucleoside inhibitors, whereby NITD-008 corresponds to an adenosine analogue while balapiravir is another nucleoside analogue originally developed for the treatment of hepatitis C virus. However, NITD-008 was terminated due to severe side effects while balapiravir failed due to its low efficiency in clinical trials [21, 22] . To search for novel antiviral peptide against the NS5 methyltranserase, Tambunan and colleagues (2014) screened over 300 commercial cyclic peptides and molecular docking results revealed two potential ligands, namely, tyr123-Prepro Endothelin and urotensin II [181] . Both peptides were shown to bind to the NS5 methyltranserase and formed stable complexes. Docking results suggested that tyr123-Prepro Endothelin was found to bind to the S-adenosyl-L-methionine (SAM) site of NS5 with a ΔG of -24.73 kkal/mol while urotensin II bound to the RNA-cap site of NS5 with a ΔG of -19.04 kkal/mol. Nevertheless, further in vitro verification is required to elucidate the antiviral potential of these inhibitors. Despite the importance of the NS5 protein, there are limited antiviral peptide screening studies targeting the NS5 protein. Perhaps this is due to the lack of a crystal structure that contains the full length of the NS5 protein. With the recent publication of the crystal structure of the NS5 protein [182] , development of antiviral peptide targeting the NS5 protein can be expected.