Prediction of antiviral drugs against African swine fever viruses based on protein-protein interaction analysis

Abstract

The African swine fever virus (ASFV) has severely influenced the swine industry of the world. Unfortunately, there is currently no effective antiviral drug or vaccine against the virus. Identification of new anti-ASFV drugs is urgently needed. Here, an up-to-date set of protein-protein interactions between ASFV and swine were curated by integration of protein-protein interactions from multiple sources. Thirty-eight swine proteins were observed to interact with ASFVs and were defined as ASFV-interacting swine proteins. The ASFV-interacting swine proteins were found to play a central role in the swine protein-protein interaction network, with significant larger degree, betweenness and smaller shortest path length than other swine proteins. Some of ASFV-interacting swine proteins also interacted with several other viruses and could be taken as potential targets of drugs for broad-spectrum effect, such as HSP90AB1. Finally, the antiviral drugs which targeted ASFV-interacting swine proteins and ASFV proteins were predicted. Several drugs with either broad-spectrum effect or high specificity on ASFV-interacting swine proteins were identified, such as Polaprezinc and Geldanamycin. Structural modeling and molecular dynamics simulation showed that Geldanamycin could bind with swine HSP90AB1 stably. This work could not only deepen our understanding towards the ASFV-swine interactions, but also help for the development of effective antiviral drugs against the ASFVs.

Keywords: ASFV; Drug; Interaction; Network; PPI; Prediction.

Figure 1. Overview of protein–protein interactions between the ASFV and swine.

(A) Collected protein–protein interactions between ASFV and swine proteins. AIP, ASFV-interacting swine proteins. (B) All the ASFV proteins involved in protein–protein interactions and the number of interacted swine proteins. PPI, protein–protein interaction.

Figure 2. The protein–protein interaction network between ASFV-interacting swine proteins and ASFV infection-associated proteins, and the topological analysis of these proteins.

(A) The protein–protein interaction network between ASFV-interacting swine proteins (AIPs) and ASFV infection-associated proteins (AAPs). (B–D) Distribution of the betweenness centrality, degree and shortest path length for all proteins (ALL), ASFV-interacting swine proteins (AIPs) and ASFV infection-associated swine proteins (AAPs) in the swine protein–protein interaction network.

Figure 3. Functional enrichment analysis of AAPs.

(A–D) Top 10 enriched terms in the domain of biological process, cellular component and molecular function and KEGG pathways were shown.

Figure 4. ASFV-interacting swine proteins and their interactions with other viruses.

(A) The protein–protein interaction network between ASFV-interacting swine proteins (AIPs) and other viruses. ASFV-interacting swine proteins were represented as ellipse in gray. Viruses were represented as squares and colored according to the legend in the bottom right. VESE, Vesicular exanthema of swine virus; Swinepox, Swinepox virus; TTSV1a, Torque teno sus virus 1a; TeschoA, Teschovirus A; Nodamura, Nodamura virus; FMDV, Foot-and-mouth disease virus; TTSVk2, Torque teno sus virus k2; FLUCV, Influenza C virus; EMCV, Encephalomyocarditis virus. (B) The number of interacted virus and the degree of ASFV-interacting swine proteins in the swine protein–protein interaction network. HISTH2AC, histone H2A type 2-C; H2A1-H, histone H2A type 1-H; HIST1H2AA, histone H2A type 1-A; HIST1H2AJ, histone H2A type 1-like; H2A2-A-L, histone H2A type 2-A-like; H2AFX, histone H2AX.

Figure 5. Predicted drugs targeting the ASFV-interacting swine proteins (AIPs) and ASFV proteins.

The interactions above and below the dotted line referred to those between drugs and ASFV-interacting swine proteins, and those between drugs and ASFV proteins, respectively. The ASFV-interacting swine proteins and ASFV proteins were represented as red and cyan circles, respectively. Drugs of protein or peptide, and those of small molecule, were represented as squares and ellipses, respectively. Drugs in the stage of approved, investigational and experimental were colored in orange, purple and light green, respectively. Drugs which specifically targeted one ASFV-interacting swine protein were highlighted in black-edge. Two drugs which targeted both the ASFV-interacting swine protein and ASFV protein were highlighted in red-edge.

Figure 6. Modelling the interactions between Geldanamycin and swine HSP90AB1.

(A) The predicted 3D structure of the Geldanamycin-binding domain of swine HSP90AB1 and its interaction with Geldanamycin. (B) RMSD of all Cα atoms for the ligand (black) and receptor-ligand complex (red) during MD simulations (10 ns).