Eco-pharma research aimed at developing COVID-19 therapeutic agent

Novel coronavirus infection disease 2019 (COVID-19) is an emerging infectious disease that has been rampant worldwide since its onset was confirmed in Wuhan, China in 2019. An effective therapy has not yet been established, and there is an urgent need to establish a breakthrough therapeutic strategy for the prevention and treatment of COVID-19 aggravation. The main route of infection is that the Spike protein (S protein) on the surface of SARS-CoV-2 binds to its recognition receptor, angiotensin converting enzyme (ACE) 2, on the host cell surface. Then, SARS-CoV-2 invades the cell via endocytosis-dependent pathway. Although the major symptom of COVID-19 is lung inflammation, ACE2 is expressed not only in the lungs but also in various tissues including heart and digestive organs. We focused on the molecular mechanism underlying the development of heart failure, a pathology involved in COVID-19 aggravation risk factors and COVID-19 squeals. We revealed that cardiac ACE2 receptors were upregulated by exposure to various environmental stresses reported as COVID-19 aggravation risk factors, and the formation of membrane protein complex between TRPC3 and NADPH oxidase (Nox) 2 that participates in myocardial remodeling underlies pathological ACE2 upregulation. Furthermore, we utilized the already approved drugs that inhibit TRPC3-Nox2 protein complex formation, and identified that clomipramine, a tricyclic antidepressant, has the best potency to suppress ACE2 internalization induced by S protein exposure. This review introduces the mechanism of pathological ACE2 receptor upregulation through TRPC3-Nox2 complex formation in the heart, and the identification of a breakthrough drug candidate using in vitro pseudo-infection screening system.