Dicycloverine for COVID-19

AbstractRecently, COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, caused > 6 million deaths. Symptoms included respiratory strain and complications, leading to severe pneumonia. SARS-CoV-2 attaches to the ACE-2 receptor of the host cell membrane to enter. Targeting the SARS-CoV-2 entry may effectively inhibit infection. Acid sphingomyelinase (ASMase) is a lysosomal protein that catalyzes the conversion of sphingolipid (sphingomyelin) to ceramide. Ceramide molecules aggregate/assemble on the plasma membrane to form “platforms” that facilitate the viral intake into the cell. Impairing the ASMase activity will eventually disrupt viral entry into the cell. In this review, we identified the metabolism of sphingolipids, sphingolipids' role in cell signal transduction cascades, and viral infection mechanisms. Also, we outlined ASMase structure and underlying mechanisms inhibiting viral entry 40 with the aid of inhibitors of acid sphingomyelinase (FIASMAs). In silico molecular docking analyses of FIASMAs with inhibitors revealed that dilazep (S = − 12.58 kcal/mol), emetine (S = − 11.65 kcal/mol), pimozide (S = − 11.29 kcal/mol), carvedilol (S = − 11.28 kcal/mol), mebeverine (S = − 11.14 kcal/mol), cepharanthine (S = − 11.06 kcal/mol), hydroxyzin (S = − 10.96 kcal/mol), astemizole (S = − 10.81 kcal/mol), sertindole (S = − 10.55 kcal/mol), and bepridil (S = − 10.47 kcal/mol) have higher inhibition activity than the candidate drug amiodarone (S = − 10.43 kcal/mol), making them better options for inhibition.

ABSTRACT The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5–7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.