Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov. 2020;6:14. Published 2020 Mar 16. doi:10.1038/s41421-020-0153-3

Review written by:

Apoorva Srinivasan, edited by Robert Parry


Green - A comprehensive study in a reputable journal

Drug repurposing, an effective drug discovery strategy when screening existing drugs, could shorten the time and reduce the cost of treatment development compared to de novo drug discovery. In this study, the authors present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, which quantifies the interplay between the HCoV–host interactome and drug targets in the human protein–protein interaction network. The overall hypothesis of the network-based methodology was (i) the proteins functionally associated with HCoVs are localized in the corresponding subnetwork and (ii) proteins that serve as drug targets for a specific disease may also be suitable drug targets for potential antiviral infection owing to common protein–protein interactions. The methodology and results are as follows:

  1. Over 2000 FDA-approved drugs known to target the HCoV-host interactome were screened for candidate repurposable drugs, and 135 drugs were computationally identified by network proximity.

  2. Out of the 135 drugs, 16 high-confidence repurposable drugs were selected against HCoVs using subject matter expertise based on: (i) strength of the network-predicted associations (ii) validation by gene set enrichment analyses; (iii) literature-reported antiviral evidence, and (iv) fewer clinically reported side effects. These 16 drugs were mostly from 4 major classes: selective estrogen receptor modulators, angiotensin receptor blockers, immunosuppressant or antineoplastic agents, or anti-inflammatory agents.

  3. Three potential drug combinations were further identified (sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) by the “Complementary Exposure” pattern: the targets of the drugs both hit the disease module, but target separate neighborhoods in the interactome, and may provide a synergistic effect.

Review Notes
 
  • All  network-predicted repurposable drugs and drug combinations must be validated in various 2019-nCoV/SARS-CoV-2 experimental assays and randomized clinical trials before being used in patients.

  • The human-nCoV interactome was formed from viruses phylogenetically related to SARS-CoV-2, but not SARS-CoV-2 itself, so some target interactions may not translate to treatment of SARS-CoV-2.

  • The network data may be incomplete, and some drug–target interactions may be functional associations instead of physical bindings.

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