Multidose evaluation of 6,710 drug repurposing library identifies potent SARS-CoV-2 infection inhibitors In Vitro and In Vivo.

Identification of host factors contributing to replication of viruses and resulting disease progression remains a promising approach for development of new therapeutics. Here, we evaluated 6710 clinical and preclinical compounds targeting 2183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target and cell interactome networking produced cellular networks important for infection. This analysis revealed 389 small molecules, >12 scaffold classes and 813 host targets with micromolar to low nanomolar activities. From these classes, representatives were extensively evaluated for mechanism of action in stable and primary human cell models, and additionally against Beta and Delta SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of novel host factor dependencies and treatments for viral diseases.

Population-scale patient safety data reveal inequalities in adverse events before and during COVID-19 pandemic

Adverse patient safety events were associated with 110 thousand deaths in the U.S. alone in 2019. The COVID-19 pandemic has further challenged the ability of healthcare systems to ensure safe medication use, and its effects on patient safety remain unknown. Here, we investigate negative outcomes associated with medication use before and during the pandemic. Using a dataset of 10,443,476 reports involving 3,624 drugs and 19,193 adverse events, we develop an algorithmic approach to analyze the pandemics impact on the incidence of drug safety events by evaluating disproportional reporting relative to the pre-pandemic time, quantifying unexpected trends in clinical outcomes, and adjusting for drug interference. Among 64 adverse events identified by our analyses, we find 54 have increased incidence rates during the pandemic, even though adverse event reporting decreased by 4.4% overall. We find clinically relevant differences in drug safety outcomes between demographic groups. Compared to male patients, women report 47.0% more distinct adverse events whose occurrence significantly increased during the pandemic relative to pre-pandemic levels. Out of 53 adverse events with a pre-pandemic gender gap, 33 have an increased gender gap during the pandemic. While musculoskeletal and metabolic side effects are disproportionately enriched in women during the pandemic, immune-related adverse events are enriched only in men. We also find the number of adverse events with an increased reporting ratio is higher in adults (by 16.8%) than in older patients (adjusted for population size). Our findings have implications for safe medication use and tie the variation in adverse events to patients that may be disproportionately affected by preventable inequities during a public health emergency.