Thioridazine 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.

AbstractCOVID-19 pandemic has infected millions of people with mortality exceeding 300,000. There is an urgent need to find therapeutic agents that can help clear the virus to prevent the severe disease and death. Identifying effective and safer drugs can provide with more options to treat the COVID-19 infections either alone or in combination. Here we performed a high throughput screen of approximately 1700 US FDA approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 24 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, and merfloquine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating wide therapeutic window compared to hydroxychloroquine which had safety index of 22 in similar experiments. Mechanistically, five of the effective compounds were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA approved compounds can provide much needed therapeutic options that we urgently need in the midst of the pandemic.

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.