Coronavirus disease 2019 (COVID-19), human erythrocytes and the PKC-alpha/-beta inhibitor chelerythrine -possible therapeutic implication

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. Until now, diverse drugs have been used for the treatment of COVID-19. These drugs are associated with severe side effects, e.g. induction of erythrocyte death, named eryptosis. This massively affects the oxygen (O₂) supply of the organism. Therefore, three elementary aspects should be considered simultaneously: (1) a potential drug should directly attack the virus, (2) eliminate virus-infected host cells and (3) preserve erythrocyte survival and functionality. It is known that PKC-α inhibition enhances the vitality of human erythrocytes, while it dose-dependently activates the apoptosis machinery in nucleated cells. Thus, the use of chelerythrine as a specific PKC-alpha and -beta (PKC-α/-β) inhibitor should be a promising approach to treat people infected with SARS-CoV-2.

Keywords: RNA polymerases; SARS-CoV-2; chelerythrine; erythrocytes; mammalian target of rapamycin complex 1 & 2 (mTORC1/-2); protein kinase C-alpha (PKC-α).

Figure 1.

Proposed mechanism of SARS-CoV-2 action and its inhibition by chelerythrine. mTORC2-dependent, mTORC1-mediated protein synthesis as well as mTORC2/PI3K-PDK1-dependent Akt activation and the resulting promotion of cell survival is the basic prerequisite for the synthesis of viral proteins and replication of its genome by the host cell biosynthetic machinery . Therefore, the inhibition of various enzymes of the host cell involved in virus production is an adequate means to stop these processes. Chelerythrine as a specific inhibitor of the protein kinases C alpha and beta (PKC-α/-β) can play an elementary role to accomplish this task. Furthermore, chelerythrine could directly inhibit the upstream kinase of the RNA polymerase of SARS-CoV-2, thus causing its inactivation