Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4

• DOI: 10.1007/s00775-022-01974-z
• Publication Date: 2022-12-09T11:02:55Z
• Authors: Daniel Oliveira S...; Rafael Aparecido ...; Marjorie Caroline...; Nathalya Cristina...; Igor Andrade Santos; Débora Moraes de ...; Nilson Nicolau Ju...; Raphael Enoque Fe...; Mark Harris; Carolina Gonçalve...; Glaucius Oliva; Ana Carolina Gome...
• Keywords: Original Paper; 0303 health sciences; Cobalt; Mechanism of action; Viral Nonstructural Proteins; Antiviral Agents; 3. Good health; Molecular Docking Simulation; 03 medical and health sciences; Molecular docking; ADME-Tox; Humans; Chikungunya Fever; Antiviral activity; Metal ion; Chikungunya virus

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease that can result in disability. Until now, there is no antiviral treatment against CHIKV, demonstrating that there is a need for development of new drugs. Studies have shown that thiosemicarbazones and their metal complexes possess biological activities, and their synthesis is simple, clean, versatile, and results in high yields. Here, we evaluated the mechanism of action (MOA) of a cobalt(III) thiosemicarbazone complex named [CoIII(L1)2]Cl based on its in vitro potent antiviral activity against CHIKV previously evaluated (80% of inhibition on replication). Furthermore, the complex has no toxicity in healthy cells, as confirmed by infecting BHK-21 cells with CHIKV-nanoluciferase in the presence of the compound, showing that [CoIII(L1)2]Cl inhibited CHIKV infection with the selective index of 3.26. [CoIII(L1)2]Cl presented a post-entry effect on viral replication, emphasized by the strong interaction of [CoIII(L1)2]Cl with CHIKV non-structural protein 4 (nsP4) in the microscale thermophoresis assay, suggesting a potential mode of action of this compound against CHIKV. Moreover, in silico analyses by molecular docking demonstrated potential interaction of [CoIII(L1)2]Cl with nsP4 through hydrogen bonds, hydrophobic and electrostatic interactions. The evaluation of ADME-Tox properties showed that [CoIII(L1)2]Cl presents appropriate lipophilicity, good human intestinal absorption, and has no toxicological effect as irritant, mutagenic, reproductive, and tumorigenic side effects.