Ebolavirus interferon antagonists—protein interaction perspectives to combat pathogenesis

Abstract

Zaire ebolavirus, one of the most pathogenic species of Ebolavirus, is a significant threat to the human community being both highly infectious and lethal. The viral proteins (VPs), specifically VP24 and VP35, antagonize the interferon (IFN) proteins accountable for human immune response. Several efforts have been made to design vaccines and therapeutics drugs. However, the success is not encouraging because of limited knowledge about the binding site information of the VPs. Such limitations stem largely from the highly infectious nature of the virus that requires specialized personnel and biosafety laboratories. As an alternative, computational techniques have also been adopted to improve the success rate of drug discovery. This article elaborates on the interactions between viral and human IFN proteins that lead to IFN antagonism. A computational framework is proposed after evaluating existing computational studies. This protein interaction and protein design-based computational framework identified critical interacting residues of the VP (VP24) responsible for the formation of a stable complex with the human KPNA5 (karyopherin alpha proteins 5). The mutations of those critical residues, as demonstrated in this article, affected the overall stability of the complex because of a sharp decrease in both the number of hydrogen bonds and possible charge-charge interactions. Therefore, we proposed that the framework could be an effective alternative to experimental work for destabilizing interactions between the VPs and human proteins responsible for IFN induction and response.

Ebola Virus VP35 Protein: Modeling of the Tetrameric Structure and an Analysis of Its Interaction with Human PKR

“…Earlier, we relied on the EvoDesign protein design framework to design EBOV VP24 residues that interact with the human KPNA5 protein. 6 EvoDesign is a structural homology driven computational protein design method, and in the present case, the structural homologs of VP35 C are considered to guide the algorithm. A residue profile based on their frequency in the structural homologs is constructed to suggest mutations during the Monte Carlo (MC) search of optimal design sequences.…”

“…Among the VPs, the EBOV-VP35 (hereafter referred to as VP35) antagonize the maximum number of human proteins involved in different IFN and ISG signaling pathways. 6 The VP35 protein, along with other structural proteins (NP and L in the presence of VP30), acts as a crucial component of the viral replication complex. VP35 interacts with a host of human proteins to specifically antagonize the RIG-I (Retinoic acid-Inducible Gene-I), TRIF (Toll/interleukin-1 Receptor domain-containing adapter Inducing IFN-β), and IRF7 (Interferon Response Factor 7) pathways.…”

“…Additionally, we validate the shortlisted complexes against the experimentally established Alanine replacements of Lys309 and Arg312 in VP35 that prevent it from antagonizing PKR autophosphorylation. 11 The recent success of protein design in identifying critical interacting residues for EBOV VP24 with human karyopherin alpha 5 (KPNA5) proteins 6 and other similar studies 12 , 13 inspired us to design the VP35 interface in search of novel hotspots, which when mutated will lead to a diminished affinity between the VP35 and PKR proteins. Toward this direction, we design the interface of VP35 protein with PKR in two residue stretches of the C-terminal (VP35 230–239 C and VP35 267–279 C ).…”

Modularity‐based parallel protein design algorithm with an implementation using shared memory programming

“…Protein design seeks to optimize the stability of a protein structure by mutating its residues. Until now, the protein design approach has been successfully applied to design proteins with increased binding affinities, 1–4 enhanced thermal stability, 5 modified enzymatic activity, 6 and also aids us to develop novel folds and enzymes having novel functionalities 7,8 …”

Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain

“…Among the viral structural proteins, viral protein 35 (VP35), viral protein 30 (VP30), nucleoprotein (NP), and RNA-dependent RNA polymerase L protein act as essential components of the viral replication complex. EBOV VP35 is also known as an interferon (IFN) antagonist that interacts with host proteins involved in multiple IFN-production pathways and multiple IFN-stimulated genes (ISGs) [7]. VP35-mediated suppression of IFN production involves a variety of host factors: VP35 inhibits IFN production by interacting with TANK-binding kinase 1 (TBK1) and inhibitor of kappa B kinase epsilon (IKKε) and by suppressing post-translational modifications of IFN regulatory factors (IRF)-3 and -7 [8].…”