Abstract
Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 µM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery.
Highlights
Fusogenic viral envelope glycoproteins are multimeric proteins that facilitate the fusion of viral and target cell lipid membranes during the initiation of infection
The results presented here indicate that the DENV E glycoprotein has multiple accessible surfaces that can be targeted by distinct inhibitors and is an amenable target for rational inhibitor design
Several of these mimic peptides did not show substantial DENV inhibitory activity [9]. These included a peptide derived from the domain II fusion sequence (DN80, corresponding to amino acids 96–114 in the dengue virus-2 (DENV-2) E protein) and two overlapping peptides derived from the domain II hinge region (DN57 and DN81, corresponding to amino acids 205–223 and 205–232, respectively)
Summary
Fusogenic viral envelope glycoproteins are multimeric proteins that facilitate the fusion of viral and target cell lipid membranes during the initiation of infection. The membrane fusion process is energetically favorable and essentially irreversible, but has a considerable kinetic energy barrier [1] These proteins allow rapid membrane fusion by drawing the opposing membranes together and either stabilizing or providing the activation energy to surmount the transition state [1,2]. In this way, they behave in many aspects like a fusion catalyst. They behave in many aspects like a fusion catalyst Because they effect a macromolecular process that involves large scale conformational changes in the substrate membranes and the proteins themselves, these proteins possess multiple interacting surfaces that could be targeted by inhibitors [3]. Inhibition of the formation of this six-helix bundle can be accomplished by exogenous peptides mimicking either of the two reciprocally interacting helices [5,6,7]
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