Thioguanine for COVID-19

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.

Significance COVID-19 is a global pandemic currently lacking an effective cure. We used a cell-based infection assay to screen more than 3,000 agents used in humans and animals and identified 15 with antiinfective activity, ranging from 0.1 nM to 50 μM. We then used in vitro enzymatic assays combined with computer modeling to confirm the activity of those against the viral protease and RNA polymerase. In addition, several herbal medicines were found active in the cell-based infection assay. To further evaluate the efficacy of these promising compounds in animal models, we developed a challenge assay with hamsters and found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens , and Mentha haplocalyx were effective against SARS-CoV-2 infection.