Drug repurposing high-throughput screen identifies candidate antiviral compounds against Puumala Orthohantavirus

Hantaviruses are zoonotic negative-sense RNA viruses that cause two severe diseases; haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) for which no approved antiviral therapies are available. To identify host-directed modulators of hantavirus infection in the available annotated drug space, we performed a drug repurposing screen in A549 cells and HUVECs, using live Puumala virus (PUUV). We identified and validated 70 drugs with antiviral activity across these 2 different cell systems. Functional clustering confirmed the known infection-inhibitory effect of several group of compounds, including inhibitors of heat shock proteins, mTOR pathway or nucleotide synthesis. In addition, we also identified compounds yet unexplored as antivirals against Hantaviruses, such as certain antibiotics. This dataset provides a systematic map of host pathways influencing PUUV infection and highlights candidate compounds and cellular processes that warrant further investigation.