Cyclopiazonic acid for COVID-19

SARS-CoV-2 infection induces non-physiological syncytia when its spike fusogenic protein on the surface of the host cells interacts with the ACE2 receptor on adjacent cells. Spike-induced syncytia are beneficial for virus replication, transmission, and immune evasion, and contribute to the progression of COVID-19. In this review, we highlight the properties of viral fusion proteins, mainly the SARS-CoV-2 spike, and the involvement of the host factors in the fusion process. We also highlight the possible use of anti-fusogenic factors as an antiviral for the development of therapeutics against newly emerging SARS-CoV-2 variants and how the fusogenic property of the spike could be exploited for biomedical applications.

AbstractTherapeutic options for coronavirus remain limited. To address this unmet medical need, we screened 5,406 compounds, including United States Food and Drug Administration (FDA)- approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6. Time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI>100), atovaquone, an anti-malarial (TI>34), and ciclosonide, an inhalable corticosteroid (TI>6). Furthermore, utilizing the severe acute respiratory syndrome CoV-2 (SARS-CoV-2), combinations of remedesivir with selected dugs were evaluated, which identified ciclosonide and nelfinavir to be additive and synergistic drugs in vitro, respectively. Together, we screened FDA-approved drugs using patient-derived MERS-CoV, triaged hits to discriminate between early and late viral life cycle inhibitors, confirmed selected drugs using SARS-CoV-2, and demonstrated the added value of selected medications in combination with remedesivir. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.