Abstract:
African swine fever (ASF) is a fatal hemorrhagic disease of domesticated pigs that is caused by the African swine fever virus (ASFV). This disease poses a threat to food security thus leading to economic losses. Presently, there are no reports of approved available vaccines for ASF. Despite the ASFV sequences having well-conserved promoter motifs, no protein with features able to bind onto the promoter TATA-like elements has been identified, nor an antiviral capable of targeting viral TATA-like elements involved in ASFV transcription. This study aimed at finding a TATA Binding Protein (TBP) and potential minor groove binders (MGBs) that can target conserved promoter motifs in ASFV. The study implemented sequence-based search methods followed by three-dimensional structure modeling. The posterior probability of fold family classification was calculated using TM-fold, and biological function was determined using TM-site, RaptorXBinding Site, Gene Ontology, and TM-align. Subsequently, congocidine congeners, Hoechst 33258, and tris-benzimidazole were selected as potential minor groove binders targeting synthetic DNA constructs containing TATA-like motifs mimicking conserved ASFV promoters. The binding scores and calculated binding energies of docked DNA-ligands complexes were evaluated. The ligand behaviour within the minor grooves was assessed using molecular dynamics (MD) simulation. The results of this study established that the three-dimensional structure of a previously uncharacterized protein pB263R had features similar to a TBP with a TM-score of 0.52, with 95% posterior probability. Additionally, the selected minor groove binders were able to significantly dock on the AT-rich regions of the synthetic DNA constructs containing TATA-like motifs. Further, calculated binding energies revealed that less cytotoxic congocidine congeners and tris-benzimidazole were an improvement of cytotoxic congocidine. The MD simulation and molecular trajectory visualization revealed that the ligands remained embedded in the minor grooves of synthetic DNA constructs during the MD simulation time course. The findings of this study suggest that these ligands may be used as potential antivirals for ASF infection in abrogating ASFV transcription. Critical for control of several ASFV genotypes.
