Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available and multitudes of antiviral treatments have been proposed and tested. Although many of the vaccines show clinical efficacy, they are not equally accessible worldwide. Additionally, due to the continuous emergence of new variants and generally short duration of immunity, the development of effective antiviral treatments remains of the utmost importance. Since the emergence of SARS-CoV-2, substantial efforts have been undertaken to repurpose existing drugs for accelerated clinical testing and emergency use authorizations. However, drug-repurposing studies using cellular assays often identify hits that later prove ineffective clinically, highlighting the need for more complex screening models. To this end, we evaluated the activity of single compounds that have either been tested clinically or already undergone extensive preclinical profiling, using a standardized in vitro model of human nasal epithelium. Furthermore, we also evaluated drug combinations based on a sub-maximal concentration of molnupiravir. We report the antiviral activity of 95 single compounds and 30 combinations. We show that only a few single agents are highly effective in inhibiting SARS-CoV-2 replication while selected drug combinations containing 10 µM molnupiravir boosted antiviral activity compared to single compound treatment. These data indicate that molnupiravir-based combinations are worthy of further consideration as potential treatment strategies against coronavirus disease 2019 (COVID-19).

The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks.

The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays. Following the successful deployment and uptake of previous open access compound collections, we assembled the Pandemic Response Box, a collection of 400 compounds to facilitate drug discovery in emerging infectious disease. These are based on public domain information on chemotypes currently in discovery and early development which have been shown to have useful activities and were prioritized by medicinal chemistry experts. They are freely available to the community as a pharmacological test set with the understanding that data will be shared rapidly in the public domain.

Actives from MMV Open Access Boxes? A suggested way forward.

It is estimated that more than 1 billion people across the world are affected by a neglected tropical disease (NTD) that requires medical intervention. These diseases tend to afflict people in areas with high rates of poverty and cost economies billions of dollars every year. Collaborative drug discovery efforts are required to reduce the burden of these diseases in endemic regions. The release of "Open Access Boxes" is an initiative launched by Medicines for Malaria Venture (MMV) in collaboration with its partners to catalyze new drug discovery in neglected diseases. These boxes are mainly requested by biology researchers across the globe who may not otherwise have access to compounds to screen nor knowledge of the workflow that needs to be followed after identification of actives from their screening campaigns. Here, we present guidelines on how to move such actives beyond the hit identification stage, to help in capacity strengthening and enable a greater impact of the initiative.

Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2.

There is an urgent need for antivirals to treat the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To identify new candidates, we screen a repurposing library of ∼3,000 drugs. Screening in Vero cells finds few antivirals, while screening in human Huh7.5 cells validates 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we find that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we find nine drugs are antiviral in respiratory cells, seven of which have been used in humans, and three are US Food and Drug Administration (FDA) approved, including cyclosporine. We find that the antiviral activity of cyclosporine is targeting Cyclophilin rather than calcineurin, revealing essential host targets that have the potential for rapid clinical implementation.