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/-ß) inhibitor should be a promising approach to treat people infected with SARS-CoV-2.
Subject(s)
Antiviral Agents/pharmacology , Benzophenanthridines/pharmacology , COVID-19 Drug Treatment , Erythrocytes/immunology , Protein Kinase C beta/antagonists & inhibitors , Protein Kinase C-alpha/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Respiratory Tract Diseases/virology , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Apoptosis/drug effects , Benzophenanthridines/adverse effects , Benzophenanthridines/therapeutic use , COVID-19/immunology , COVID-19/metabolism , DNA-Directed RNA Polymerases/metabolism , Erythrocytes/drug effects , Erythrocytes/metabolism , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 2/metabolism , Protein Biosynthesis/drug effects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , RNA Viruses/genetics , RNA Viruses/metabolism , Respiratory Tract Diseases/enzymology , Respiratory Tract Diseases/metabolismABSTRACT
INTRODUCTION: Type II transmembrane serine proteases (TTSPs) of the human respiratory tract generate high interest owing to their ability, among other roles, to cleave surface proteins of respiratory viruses. This step is critical in the viral invasion of coronaviruses, including SARS-CoV-2 responsible for COVID-19, but also influenza viruses and reoviruses. Accordingly, these cell surface enzymes constitute appealing therapeutic targets to develop host-based therapeutics against respiratory viral diseases. Additionally, their deregulated levels or activity has been described in non-viral diseases such as fibrosis, cancer, and osteoarthritis, making them potential targets in these indications. AREAS COVERED: Areas covered: This review includes WIPO-listed patents reporting small molecules and peptide-based inhibitors of type II transmembrane serine proteases of the respiratory tract. EXPERT OPINION: Expert opinion: Several TTSPs of the respiratory tract represent attractive pharmacological targets in the treatment of respiratory infectious diseases (notably COVID-19 and influenza), but also against idiopathic pulmonary fibrosis and lung cancer. The current emphasis is primarily on TMPRSS2, matriptase, and hepsin, yet other TTSPs await validation. Compounds listed herein are predominantly peptidomimetic inhibitors, some with covalent reversible mechanisms of action and high potencies. Their selectivity profile, however, are often only partially characterized. Preclinical data are promising and warrant further advancement in the above diseases.