Drug repurposing for therapeutic discovery against human metapneumovirus infection

Abstract

Human metapneumovirus (HMPV) is recognised as an important cause of pneumonia in infants, elderly, and immunocompromised individuals worldwide. The absence of an antiviral treatment or vaccine strategy against HMPV infection creates a high burden on the global health care system. Drug repurposing has become increasingly attractive for the treatment of emerging and endemic diseases as it requires less research and development costs than traditional drug discovery. In this study, we developed an in vitro medium-throughput screening assay that allows for the identification of novel anti-HMPV drugs candidates. Out of [~]2400 compounds, we identified eleven candidates with a dose-dependent inhibitory activity against HMPV infection. Additionally, we further described the mode of action of five anti-HMPV candidates with low in vitro cytotoxicity. Two entry inhibitors, Evans Blue and aurintricarboxylic acid, and three post-entry inhibitors, mycophenolic acid, mycophenolate mofetil, and 2,3,4-trihydroxybenzaldehyde, were identified. Among them, the mycophenolic acid series displayed the highest levels of inhibition, due to the blockade of intracellular guanosine synthesis. Importantly, MPA has significant potential for drug repurposing as inhibitory levels are achieved below the approved human oral dose. Our drug-repurposing strategy proved to be useful for the rapid discovery of novel hit candidates to treat HMPV infection and provide promising novel templates for drug design. HighlightsO_LIThere is currently no treatment against acute HMPV infection. C_LIO_LIWe developed a medium-throughput screening for drug repurposing against HMPV infection. C_LIO_LIEvaluation of a large drug library identified 5 candidates with low M to nM IC50 values against HMPV growth. C_LIO_LIThe approved drug mycophenolic acid (MPA) is a nM inhibitor of HMPV in vitro infection C_LIO_LIHuman MPA plasma levels upon oral dosing are 10x higher than MPA IC50 against HMPV in vitro infection. C_LI