A Peptide Inhibitor Derived from the Conserved Ectodomain Region of DENV Membrane (M) Protein with Activity Against Dengue Virus Infection

Abstract

© 2015 John Wiley & Sons A/S. Dengue virus (DENV) infection is a public health problem worldwide; thus, the development of a vaccine and anti-DENV drugs is urgently needed. It has been observed that low levels of viremia in DENV-infected individuals are associated with mild disease outcomes; therefore, reduction of DENV load should offer therapeutic benefits. Disruption of protein-protein interactions on the surface of DENV by a peptide that mimics part of its structural protein may affect stability of the virion structure and inhibit viral entry into host cells. To test this hypothesis, we generated a novel peptide inhibitor that mimics the conserved ectodomain region of DENV membrane (M) protein, MLH40 peptide, for DENV inhibition assays. MLH40 inhibited all four serotypes of the virus (DENV1-4) at half maximal inhibition concentration of 24-31 μm. MLH40 at 100 μm blocked DENV2 attachment to cells by 80%. The inhibitory activity of MLH40 against DENV was consistently observed with different cell types, including Vero, A549, and Huh7 cells. Prediction of MLH40 binding by a molecular docking program indicated that its N-terminal loop may interact with DENV envelope (E) proteins and alter their dimer conformation. Thus, MLH40 may serve as a lead-peptide inhibitor for the development of an anti-DENV drug. The interaction of two dengue virus (DENV) surface proteins, envelope (E) and membrane (M), is important for virus stability and infectivity. We synthesized a peptide inhibitor mimicking DENV M protein (MLH40) to interfere the E-M protein interaction. MLH40 peptide in micromolar ranges inhibited four DENV serotypes in the in vitro experiments. This finding suggested that MLH40 is potential for further development as anti-DENV drug.