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Drug Repurposing for SARS-CoV-2 Using Network Polypharmacological Approach

Posted on June 9th, 2020 by in COVID-19

Drug development is a multidisciplinary field that requires a drug to successfully pass through different stages — from chemical design to biological experimentation on cells and animals, and finally three phases of human clinical trials — before being approved by the FDA for clinical administration. However, following such a path would not be feasible under circumstances where rapid discoveries are required, such as in the case of the current SARS-CoV-2 outbreak. Hence, repurpose of already approved FDA drugs could help in such circumstances, which can save effort, time and money.

In this regard, network medicine (NM) has proved to be a potential cornerstone in drug discovery and repurposing1. Indeed, NM has provided a platform to identify the molecular complexity of particular diseases and has helped decipher the molecular relationships among distinct diseases and drug targets. For example, we can identify treatments to a specific disease based on its underlying molecular mechanisms that could be targets for potential therapeutics.

Three main drug target strategies exist for SARS-CoV-22,3: (1) block entry of the virus into the host, (2) block replication inside the host and (3) reduce the undirected inflammatory response in the host. Angiotensin-converting enzyme 2 (ACE2), the receptor protein in host cells responsible for mediating SARS-CoV-2 infection, is a critical enzyme that also mediates local anti-inflammatory pathways within human tissues. Although several ACE2 inhibitors are available in the market, it is not clear yet if such treatments would worsen the undirected inflammatory response of the host.

On the other hand, while the molecular signature of SARS-CoV-2 is still under investigation, we thought it would be useful to determine the interactions of drugs with key proteins related to other coronaviruses, such as SARS-CoV-1 and MERS-CoV. The molecular pathways and genetic signatures associated with inflammatory responses in human host cells are also well characterized, and exploring those can provide valuable insights. We therefore aimed to identify a treatment, using network medicine and polypharmacology, that could inhibit viral entry and replication, as well as the endogenous immune response of the host.

Pathway Studio, a biomedical database derived from relationships extracted from more than 30 million academic manuscripts, was first used to create a biological knowledge graph that was employed to develop a model that could predict links between drugs, proteins (genes) and diseases caused by other coronavirus (i.e. SARS-CoV-1 and MERS-CoV).

First, we used this model to predict down-regulators of processes that SARS-CoV-1 and MERS-CoV rely on, as well as ACE2, and then the top regulators of autophagy, a biological process in the host cell known to play a significant role in controlling viral infection. Next, we used FDA-approved drug combinations to identify potential complementary combinations for disease regulation, which were further explored for their possible regulatory actions on biological processes and molecular functions deregulated in the disease state of SARS-CoV-1 and MERS-CoV. After that, we identified hub proteins/genes in these deregulated pathways, which we proposed as key regulators linking drug mechanisms to disease state. Finally, we provided a simplified sub-graph of our biomedical knowledge graph showing possible drug regulatory interactions with SARS-CoV-1 and MERS-CoV through key regulatory genes.

We hope that our simplified graph will help researchers in understanding the mechanistic pathways of SARS-CoV-2 and aid in the fruitful development of efficient treatments using synergistic and complementary drug combinations of drugs that are able to target both viral infection and immunomodulatory pathways. The full study, A Network Polypharmacology Approach to Drug Repurposing for SARS-CoV-2, is currently under journal review, so we will let you know in this blog when it has been published.

REFERENCES:

1. Barabási, A.-L., Gulbahce, N. & Loscalzo, J. Network medicine: a network-based approach to human disease. Nat. Rev. Genet. 12, 56–68 (2011).

2. Jakovac, H. COVID-19 – is the ACE2 just a foe? Am. J. Physiol. Lung Cell Mol. Physiol. (2020) doi:10.1152/ajplung.00119.2020.

3. Quartuccio, L., Semerano, L., Benucci, M., Boissier, M.-C. & De Vita, S. Urgent avenues in the treatment of COVID-19: Targeting downstream inflammation to prevent catastrophic syndrome. Joint Bone Spine 87, 191–193 (2020).

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