Fig. 1.

Network medicine framework for drug repurposing. (A) Study design and timeline. Following the publication of host–pathogen PPIs (21) (March 23, 2020), we implemented three drug-repurposing algorithms, relying on AI (A1 to A4), network diffusion (D1 to D5), and proximity (P1 to P3), together resulting in 12 predictive ranking lists (pipelines, shown in B). Each pipeline offers predictions for a different number of drugs that were frozen on April 15, 2020. We then identified 918 drugs for which all pipelines but P3 offered predictions, and experimentally validated their effect on the virus in VeroE6 cells (18). The experimental (E918, E74) and clinical trial lists C415 offered the ground truth for validation and rank aggregation. (C) Direct target drugs bind either to a viral protein (D1) or to a host protein target of the viral proteins (D2). Network drugs (D3), in contrast, bind to the host proteins and limit viral activity by perturbing the host subcellular network.