Evolution Mechanism And Antiviral Drug Prediction Of African Swine Fever Viruses

African swine fever(ASF)is a severe swine infectious disease caused by African swine fever virus(ASFV).It has caused great losses to the global pig industry.ASFV has complex genetic and evolutionary mechanisms,which hinder the development of effective vaccines and drugs for the prevention and control of the virus.In this thesis,the evolution mechanism and antiviral drugs of ASFV were studied,and the main findings were listed as follows:1)The ASFV genomes had large genetic diversities which were mainly caused by extensive genomic insertions and/or deletions(indels).Analyses showed that the indels may be attributed much to the homologous recombination.The homologous recombination not only leads to changes in genome size,but also changes of gene content of ASFVs.Further analysis showed that repeated elements of dozens of nucleotides in length were widely distributed and clustered in the adjacent positions of ASFV genomes,which may facilitate the occurrence of homologous recombination.This work highlighted the importance of homologous recombination in shaping the genetic diversity of the ASFVs,and could help understand the evolution of the virus.2)The MGF proteins of ASFVs were classified into 31 groups based on protein sequence homology and network clustering.A web server named MGFC for classifying MGF proteins was established and kept available for free at http://www.computatio nalbiology.cn/MGF/home.html.Then,the MGF proteins were characterized by groups.Results showed that MGF groups of the same family were most similar to each other and had conserved sequence motifs;the genetic diversity of MGF groups varied widely,mainly due to the occurrence of indels.In addition,the MGF proteins were predicted to have large structural and functional diversity,and MGF proteins of the same MGF family tended to have similar structure,location and function.Reconstruction of the ancestral states of MGF groups along the ASFV phylogeny showed that most MGF groups experienced either the copy number variations or the gain-or-loss changes.It is found that the copy number decrease and the loss of MGF groups were much larger than the copy number increase and the gain of MGF groups,respectively,suggesting the ASFV tended to lose MGF proteins in the evolution.Overall,the work provides a detailed classification for MGF proteins and would facilitate further research on MGF proteins.3)The antiviral drugs against ASFVs were predicted based on a strategy of targeting host protein.Firstly,an up-to-date set of protein-protein interactions between ASFV and swine were curated by integration of protein-protein interactions from multiple sources.The ASFV-interacting swine proteins were found to play a central role in the swine protein-protein interaction network,with significantly 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.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 the development of effective antiviral drugs against the ASFVs.In conclusion,this thesis found that the genetic diversity of ASFV was mainly contributed by homologous recombination;built a classification system for MGF proteins and further systematically characterized the MGF proteins;built the PPI network between ASFVs and swine,and predcited antiviral drugs against ASFVs.It not only helps understand the evolutionary mechanisms of ASFV,but also facilitates the development effective vaccines and drugs against the virus.