Inhibition of the Dimerization of SARS-COV-2 Encoded Nucleocapsid Protein by Chlorophyll A, Halothane and Tetraethylene Glycol Monooctyl Ether

Abstract

SARS-COV-2 is the etiologic agent of COVID-19. There is currently no effective remedy for SARS-COV-2 infections or COVID-19. Dimerization of SARS-COV-2 encoded Nucleocapsid protein (NCp) is a prerequisite step for it to act as an essential co-factor for the replication, transcription and packaging of SARS-COV-2 genome. Molecules that prevent the dimerization of NCp are potential prophylactics and therapeutics for the control of SARS-COV-2 infections and virulence. Here, through interrogation of chemical ligand data banks and thermodynamic calculations, we show that Chlorophyll A, Halothane and Tetraethylene glycol monooctyl ether (TGME) are inhibitors of the dimerization of NCp. Chlorophyll A is the most potent inhibitor of NCp dimerization with dissociation constant (K D ) of ~28 pM. Chlorophyll A binding caused the dissociation constant (K D ) for NCp-NCp interaction to increase from ~7.2 pM to ~1000000 pM. Chlorophyll A also bound to NCp mutated at phosphorylation sites S186, S197 and S202 (S186F, S197L and S202N) and phosphorylation recognition sites RNpSTP, (S197L) and RGTpSP (RG203/204KR and RG203/204KT) with dissociation constants of ~12 pM, ~6.1 pM, ~27.8. pM, ~27.8 pM and ~2.2 pM respectively. These results show that Chlorophyll A, a chemical ligand that is present in high abundance with good absorption properties and near-zero toxicity is a potential very potent prophylactic and therapeutic that acts via disruption of NCp dimerization.