No Shortcuts to SARS-Cov-2 Antivirals

Repurposing existing drugs has not yet yielded any effective treatments for COVID-19, say Aled Edwards and Ingo Hartung in a Perspective, even though billions of dollars have already been spent on “hypothesis-free” drug repurposing for COVID-19 antivirals. “[I]t would be wise to increase investments toward the rational development of new direct-acting antiviral drugs,” they write. “Although this approach may take more time, it is less risky and can even be used to develop drugs for newly emerging viruses.” Edwards and Hartung highlight a 22 June Science study by Tummino et al. that reported that a class of repurposed drugs that had showed an antiviral effect against SARS-CoV-2 in cells were functioning non-specifically through phospholipidosis, and so were an artifact – unlikely to be effective in vivo. Tummino et al. found this artifact to arise with multiple repurposed drugs that have been tested in patients – including hydroxychloroquine. Edwards and Hartung say this and related studies are a warning that even amid the pressure of a pandemic, scientific thoroughness is still essential. They recommend all screening hits be treated with extreme skepticism, whether they derive from a biochemical or cell-based assay and whether they are new compounds or approved drugs. They highlight the challenge it is for drug screens to flag compounds that act subtly or through yet unknown confounding mechanisms, noting that this challenge can often be overcome by care­fully exploring structure-activity relation­ships (SARs). “Exploring the SAR is exactly what Tummino et al. did,” say the authors, “and their diligence was rewarded by falsifying a compelling target hypothesis without investing money and the hopes and health of patients into a clinical study.”