Bioscience Evidence 2024, Vol.14, No.5, 227-237 http://bioscipublisher.com/index.php/be 231 4.2 Mechanisms of action and inhibition strategies The mechanisms of action and inhibition strategies for targeting ASFV proteins are diverse and tailored to the specific functions of the proteins. One common strategy is the inhibition of viral entry and replication. For example, targeting endosomal membrane proteins involved in the virus's entry pathway has shown significant inhibition of ASFV, as well as other viruses like Ebola and SARS-CoV-2 (Galindo et al., 2020). This approach leverages the commonalities in the entry mechanisms of different viruses to develop broad-spectrum antivirals. Another strategy involves the direct inhibition of viral enzymes essential for replication. The pS273R protease, for instance, can be inhibited by compounds identified through virtual screening and molecular dynamics simulations, which disrupt the enzyme's active site and prevent the proteolysis of viral polyproteins (Lu et al., 2023). Similarly, the stabilization of G-Quadruplexes in the ASFV genome by ligands such as N-Methyl Mesoporphyrin (NMM) and pyridostatin (PDS) can inhibit the expression of essential viral genes, thereby reducing viral replication (Muturi et al., 2021). Inhibition of immune evasion mechanisms is also a critical strategy. ASFV proteins that interfere with the host's IFN response, such as A276R, A528R, and I329L, can be targeted to enhance the host's antiviral defenses. For example, the deletion of these genes from the virus can lead to a stronger IFN response, potentially resulting in an attenuated virus that could be used as a vaccine (Correia et al., 2013; Correia et al., 2023). Additionally, the dual action of the I329L protein in inhibiting multiple Toll-like receptor (TLR) pathways presents an opportunity to develop inhibitors that can restore the host's innate immune response (Correia et al., 2023). 5 Case Studies 5.1 Case study 1: DNA polymerase X DNA Polymerase X is a crucial enzyme in the replication machinery of African swine fever virus (ASFV). It plays a significant role in the virus's ability to replicate its DNA within the host cells. The structural analysis of ASFV DNA Polymerase X has revealed unique features that differentiate it from other polymerases, making it a potential target for antiviral drug development. The enzyme's active site and its interaction with DNA substrates have been characterized, providing insights into its mechanism of action and potential inhibition strategies (Wang et al., 2021). 5.2 Case study 2: p72 major capsid protein The p72 major capsid protein is the most abundant structural protein in ASFV, forming the outermost icosahedral capsid of the virion. Recent studies have identified nanobodies against the p72 protein, which were screened from a camelid immune VHH library using phage display techniques. Among the identified nanobodies, Nb25 showed the highest affinity to both recombinant and native p72 protein. Nb25's long CDR3 region allows it to access hidden epitopes, making it a valuable tool for diagnostic and therapeutic applications. The specificity and high affinity of Nb25 to p72 suggest its potential use in biosensors and immunoassays for ASFV detection (Yang et al., 2020). 5.3 Case study 3: dUTPase Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is an essential enzyme for ASFV replication, catalyzing the hydrolysis of dUTP to dUMP. Structural studies of ASFV dUTPase (E165R) have provided detailed insights into its active site configuration, which is highly similar to dUTPases from other pathogens like Plasmodium falciparum and Mycobacterium tuberculosis (Figure 2). This similarity suggests that existing inhibitors for these pathogens could be repurposed for ASFV. Additionally, monoclonal antibodies targeting specific antigenic regions of ASFV dUTPase have been developed, showing inhibitory effects on the enzyme's activity. These findings highlight dUTPase as a promising target for antiviral drug development against ASFV (Li et al., 2019; Zhang et al., 2021).
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