Abstract
The Crimean-Congo Hemorrhagic Fever virus (CCHFV) is a segmented negative single-stranded RNA virus (−ssRNA) which causes severe hemorrhagic fever in humans with a mortality rate of ~50%. To date, no vaccine has been approved. Treatment is limited to supportive care with few investigational drugs in practice. Previous studies have identified viral RNA dependent RNA Polymerase (RdRp) as a potential drug target due to its significant role in viral replication and transcription. Since no crystal structure is available yet, we report the structural elucidation of CCHFV-RdRp by in-depth homology modeling. Even with low sequence identity, the generated model suggests a similar overall structure as previously reported RdRps. More specifically, the model suggests the presence of structural/functional conserved RdRp motifs for polymerase function, the configuration of uniform spatial arrangement of core RdRp sub-domains, and predicted positively charged entry/exit tunnels, as seen in sNSV polymerases. Extensive pharmacophore modeling based on per-residue energy contribution with investigational drugs allowed the concise mapping of pharmacophoric features and identified potential hits. The combination of pharmacophoric features with interaction energy analysis revealed functionally important residues in the conserved motifs together with in silico predicted common inhibitory binding modes with highly potent reference compounds.
Highlights
The Crimean-Congo hemorrhagic fever (CCHF) is a devastating viral infection with an extremely high case-to-fatality ratio[1] caused by a tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) from the genus Nairovirus (Family Orthonairovirus, order Bunyaviridae)[2,3,4]
High-resolution RNA-dependent RNA polymerase (RdRp) structures were examined from segmented negative single-stranded RNA viruses (−ssRNA, order Bunyaviridae) including La Crosse orthobunyavirus (LaCV) (PDB ID: 5amr, 5amq) and Influenza A and B (4wsb, 4wrt)
T-705 has proven historically reliable in reducing CCHF viremia and has been found to be the most efficacious drug from a cohort of similar agents when used against a variety of Crimean-Congo Hemorrhagic Fever virus (CCHFV) strains[130,168]
Summary
The Crimean-Congo hemorrhagic fever (CCHF) is a devastating viral infection with an extremely high case-to-fatality ratio (ranging from 5–30%, and 50–80% during epidemic events)[1] caused by a tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) from the genus Nairovirus (Family Orthonairovirus, order Bunyaviridae)[2,3,4]. Together with viral RNA (vRNA), NP and RdRp form the genomic ribonucleoprotein complexes (RNPs)[13], CCHFV viral entry, transcription/replication cycle, glycoprotein maturation and viral assembly have been recently and extensively reviewed[10,14,15]. In all Nairovirus, the RdRp domain maintains six characteristic conserved motifs including PreA/F, A, B, C, D, and E in the central region[19,20,21,22] Most of these motifs are located in the palm subdomain and define the formation of the active site[21]. CCHFV has a complex genome with multiple proteins involved in processes ranging from virus entry into host cells to viral replication and suppression of the host immune system[10]. RdRp has a pivotal role in the replication process and is involved in the crucial association of viral RNA to make RNP complexes[15]
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