Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2
Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin & Feixiong Cheng
Introduction
Coronaviruses (CoVs) typically affect the respiratory tract of mammals, including humans, and lead to mild to severe respiratory tract infections1. In the past two decades, two highly pathogenic human CoVs (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), emerging from animal reservoirs, have led to global epidemics with high morbidity and mortality2. For example, 8098 individuals were infected and 774 died in the SARS-CoV pandemic, which cost the global economy with an estimated $30 to $100 billion3,4. According to the World Health Organization (WHO), as of November 2019, MERS-CoV has had a total of 2494 diagnosed cases causing 858 deaths, the majority in Saudi Arabia2. In December 2019, the third pathogenic HCoV, named 2019 novel coronavirus (2019-nCoV/SARS-CoV-2), as the cause of coronavirus disease 2019 (abbreviated as COVID-19)5, was found in Wuhan, China. As of 24 February 2020, there have been over 79,000 cases with over 2600 deaths for the 2019-nCoV/SARS-CoV-2 outbreak worldwide; furthermore, human-to-human transmission has occurred among close contacts6. However, there are currently no effective medications against 2019-nCoV/SARS-CoV-2. Several national and international research groups are working on the development of vaccines to prevent and treat the 2019-nCoV/SARS-CoV-2, but effective vaccines are not available yet. There is an urgent need for the development of effective prevention and treatment strategies for 2019-nCoV/SARS-CoV-2 outbreak.
Although investment in biomedical and pharmaceutical research and development has increased significantly over the past two decades, the annual number of new treatments approved by the U.S. Food and Drug Administration (FDA) has remained relatively constant and limited7. A recent study estimated that pharmaceutical companies spent $2.6 billion in 2015, up from $802 million in 2003, in the development of an FDA-approved new chemical entity drug8. Drug repurposing, represented as an effective drug discovery strategy from existing drugs, could significantly shorten the time and reduce the cost compared to de novo drug discovery and randomized clinical trials9,10,11. However, experimental approaches for drug repurposing is costly and time-consuming12. Computational approaches offer novel testable hypotheses for systematic drug repositioning9,10,11,13,14. However, traditional structure-based methods are limited when three-dimensional (3D) structures of proteins are unavailable, which, unfortunately, is the case for the majority of human and viral targets. In addition, targeting single virus proteins often has high risk of drug resistance by the rapid evolution of virus genomes1.
Viruses (including HCoV) require host cellular factors for successful replication during infection1. Systematic identification of virus–host protein–protein interactions (PPIs) offers an effective way toward elucidating the mechanisms of viral infection15,16. Subsequently, targeting cellular antiviral targets, such as virus–host interactome, may offer a novel strategy for the development of effective treatments for viral infections1, including SARS-CoV17, MERS-CoV17, Ebola virus18, and Zika virus14,19,20,21. We recently presented an integrated antiviral drug discovery pipeline that incorporated gene-trap insertional mutagenesis, known functional drug–gene network, and bioinformatics analyses14. This methodology allows to identify several candidate repurposable drugs for Ebola virus11,14. Our work over the last decade has demonstrated how network strategies can, for example, be used to identify effective repurposable drugs13,22,23,24,25,26,27 and drug combinations28 for multiple human diseases. For example, network-based drug–disease proximity sheds light on the relationship between drugs (e.g., drug targets) and disease modules (molecular determinants in disease pathobiology modules within the PPIs), and can serve as a useful tool for efficient screening of potentially new indications for approved drugs, as well as drug combinations, as demonstrated in our recent studies13,23,27,28.
In this study, we present an integrative antiviral drug repurposing methodology, which combines a systems pharmacology-based network medicine platform that quantifies the interplay between the virus–host interactome and drug targets in the human PPI network. The basis for these experiments rests on the notions that (i) the proteins that functionally associate with viral infection (including HCoV) are localized in the corresponding subnetwork within the comprehensive human PPI network 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 PPIs and functional pathways elucidated by the human interactome (Fig. 1). We follow this analysis with bioinformatics validation of drug-induced gene signatures and HCoV-induced transcriptomics in human cell lines to inspect the postulated mechanism-of-action in a specific HCoV for which we propose repurposing (Fig. 1).
Our network-based methodology combines a systems pharmacology-based network medicine platform that quantifies the interplay between the virus–host interactome and drug targets in the human PPI network. a Human coronavirus (HCoV)-associated host proteins were collected from literatures and pooled to generate a pan-HCoV protein subnetwork. b Network proximity between drug targets and HCoV-associated proteins was calculated to screen for candidate repurposable drugs for HCoVs under the human protein interactome model. c, d Gene set enrichment analysis was utilized to validate the network-based prediction. e Top candidates were further prioritized for drug combinations using network-based method captured by the “Complementary Exposure” pattern: the targets of the drugs both hit the HCoV–host subnetwork, but target separate neighborhoods in the human interactome network. f Overall hypothesis of the network-based methodology: (i) the proteins that functionally associate with HCoVs are localized in the corresponding subnetwork within the comprehensive human interactome network; 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 elucidated by the human interactome.