Network Medicine Framework for Identifying Drug Repurposing Opportunities for COVID-19

Abstract

The current pandemic has highlighted the need for methodologies that can quickly and reliably prioritize clinically approved compounds for their potential effectiveness for SARS-CoV-2 infections. In the past decade, network medicine has developed and validated multiple predictive algorithms for drug repurposing, exploiting the sub-cellular network-based relationship between a drug's targets and disease genes. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs that had been experimentally screened in VeroE6 cells, and the list of drugs under clinical trial, that capture the medical community's assessment of drugs with potential COVID-19 efficacy. We find that while most algorithms offer predictive power for these ground truth data, no single method offers consistently reliable outcomes across all datasets and metrics. This prompted us to develop a multimodal approach that fuses the predictions of all algorithms, showing that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We find that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these drugs rely on network-based actions that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.

Figure 1. Network Medicine Framework for Drug Repurposing.

(A) Study Design and Timeline. Following the publication of host-pathogen protein-protein interactions – March, 23^rd, 2020 – we implemented three drug repurposing algorithms, relying on AI (A1-A4), network diffusion (D1-D5) and proximity (P1-P3), together resulting in 12 predictive ranking lists (pipelines, shown in (B)). Each pipeline offers predictions for a different number of drugs, what 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. 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.

Figure 2.. COVID-19 Disease Module.

(A) Proteins targeted by SARS-CoV-2 are not distributed randomly in the human interactome, but form a large connected component (LCC) consisting of 208 proteins, and multiple small subgraphs, shown in the figure. Almost all proteins in SARS-CoV-2 LCC are also expressed in the lung tissue, potentially explaining the effectiveness of the virus in causing pulmonary manifestations of the disease. (B) The random expectation of the LCC size indicates that the observed COVID-19 LCC, whose size is indicated by the red arrow, is larger than expected by chance (Z-score=1.65). (C) Heatmap of the Kendall τ statistic showing that the ranking list predicted by the different methods (A,D,P) are not correlated. We observe, however high correlations among the individual ranking list predicted by the same predictive method.

Figure 3. Experimental Outcomes and Network Origins.

(A) Examples of dose-response curves for eight of the 918 experimentally validated drugs, illustrating the four observed outcomes (S, W, C and N). VeroE6 cells were challenged in vitro with SARS-CoV-2 virus and treated with the drug over a range of doses (from 8 nM to 8 μM). A two-steps drug-response model (see SI Section 2.3) was used to classify each drug into Strong, Weak, Cytotoxic or No-Effect categories, according to their response to the drug in different doses and cell and viral reduction. (B) The sub-network formed by the targets of the 77 S&W drugs within the interactome. The link corresponds to binding interactions. Purple proteins are targeted by S drugs only; orange by W drugs only; proteins targeted by both S&W drugs are shown as pie charts, proportional to the number of targets in each category. (C) The targets of N drugs have a positive proximity Z-Score to the COVID-19 module, meaning they are further from the COVID-19 module than random expectation. By contrast, the targets of S&W drugs are more proximal (closer) to the COVID-19 module than expected by change, suggesting that their COVID-19 vicinity contribute to their ability to alter the virus’s ability to infect the cells.

Figure 4. Performance of the Predictive Pipelines.

(A,B) AUC (Area under the Curve), (C,D) Precision at 100, and (E,F) Recall at 100, for twelve pipelines tested for drug repurposing, each plot using as a gold standard the S&W drugs in E918 (left column) and drugs under clinical trials for treating COVID-19 as of April 15^th, 2020 (CT415, right column). (G,H) The top K precision and recall for the different rank aggregation methods (connected points), compared to the individual pipelines (empty symbols) documenting the consistent predictive performance of CRank. Similar results are shown for two other datasets in Figure S8: the prospective expert curated E74 and the clinical trial data refreshed on 06/15/20 (CT615)