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Five drug development strategies to combat 2019 novel coronavirus

Posted on April 15th, 2020 by in COVID-19

This article was originally published on Feb 28, 2020, and has been updated on Apr 13, 2020.

Coronavirus disease 19 (COVID-19) has rapidly spread from its starting point in Wuhan, China. As of February 23, 2020, a total of 32 countries and territories have reported 78,811 cases (98% in China) and 2462 deaths [1]. The international scientific community is in a race against time. Researchers across the globe are collaborating to develop antivirals and vaccines to contain the spread of 2019 novel coronavirus (SARS-CoV-2).

I personally would like to contribute to this international effort by sharing some ideas on how to use Elsevier’s Life Sciences Solutions to speed drug development to combat COVID-19. Here are five drug development strategies that researchers should try.

1. Leverage drugs and biomolecules previously reported to have activity against related coronaviruses

SARS-CoV-2 and severe acute respiratory syndrome–associated coronavirus (SARS-CoV) have >90% sequence identity in their essential enzymes [2] and share the same entry receptor [3]. Their close genetic relationship suggests that drugs effective against SARS-CoV (and potentially other coronaviruses) might be effective against SARS-CoV-2.

Using Elsevier’s Biology Knowledge Graph (aka Pathway Studio), researchers can quickly explore drug repurposing options by reviewing previously published information on coronavirus protein interactions and checking a list of drugs that interfere with those interactions.

Through Pathway Studio, we found 98 drugs and biomolecules that were previously described as effective against other coronaviruses, including SARS-CoV-1. Many of these drug candidates likely hold merit but were not approved to treat coronavirus infection because the previous coronavirus outbreaks ended before drug candidate testing could be completed. Several of these drugs and biomolecules are already in clinical trials and being tested for their activity against COVID-19.

2. Search for substances that interact with multiple proteins from related coronaviruses

Reaxys Medicinal Chemistry (RMC) provides normalized substance­–target affinity data and pharmacokinetic, efficacy, toxicity, safety, and metabolic profiles. Using RMC, we identified 393 substances that interacted with 25 targets on 6 different coronaviruses (SARS-CoV, Middle East respiratory syndrome [MERS] coronavirus, human coronavirus 229E, Coronaviridae, and Coronavirinae) with a <1 mM affinity. These 25 targets mainly comprise three proteins encoded by the coronavirus genome: the main protease (which cleaves virus preproprotein into 16 different active proteins), the papain-like transmembrane protease (which cleaves viral preproprotein and also deubiquitinates human proteins), and components of the viral RNA replicase.

These compounds can be used to perform virtual docking experiments against the predicted structures of SARS-CoV-2 proteins or as lead compounds for in-vitro combinatorial screening against recombinant SARS-CoV-2 proteins to develop new drugs.

3. Investigate compounds that target autophagy

Autophagy is a pathway used by cells to recycle damaged proteins and destroy pathogens, but some viruses can hijack the autophagy pathway to manufacture virus proteins [4]. Therefore, whether autophagy inhibition or activation would be more effective against SARS-CoV-2 infection needed further exploration.

We used Pathway Studio and found 406 compounds that inhibited and 802 compounds that activated autophagy. In total, 33 of the compounds that activated (and none of the compounds that inhibited) autophagy were listed among the 121 drugs reported effective against coronaviruses. In addition, Gassen et al. found that blocking autophagy attenuation inhibited MERS coronavirus replication [5]. Both these findings suggest that activation of autophagy inhibits SARS-CoV-2 replication and autophagy-activating compounds should be investigated as antivirals.

The drug combination chloroquine + azithromycin (both autophagy inhibitors) is gaining popularity as a COVID-19 treatment. Inhibition of autophagy blocks virus entry into cells but also blocks antigen presentation by macrophages, which blocks activation of adaptive immunity with both T cells and B cells. Thus, autophagy inhibitors might be best given after the adaptive immune response against the virus develops, which usually takes 4-7 days after disease onset.

4. Targeting human proteases involved in activation viral Spike protein

We have identified 12 human proteases that can cleave and activate SARS-CoV Spike protein. Three are transmembrane proteases, two are secreted proteases and seven are intracellular endoplasmic reticulum proteases. The intracellular ER proteases can continue to activate Spike and induce viral membrane fusion after initial endocytosis activated by extracellular proteases. Three drugs capable of inhibiting several extracellular proteases (camostat, nafamostat, and cobicistat) are now in clinical trials (in Germany, Japan and China, respectively). Compounds with broader specificity and the ability to inhibit all 12 proteases can be developed by using polypharmacologic methods.

5. Drugs targeting receptor-mediated endocytosis and viral budding

Receptor-mediated endocytosis is the process that virus uses to enter the cell preceding autophagy. SARS-CoV can direct early endosomes into autophagy during endosome sorting instead of endosome recycling back to plasma membrane. Endocytosis and endosome sorting are complex process that involves more than 50 human proteins. Several of these proteins such as AAK1 and GAK1 are druggable and have known drugs inhibiting them. Viral budding exploits late endosome to Goldgi transport event to secrete assembled viral particles outside the host cell.  It involves more than 30 human proteins, and several of them are also druggable.

Links to the lists of potential SARS-CoV-2 drug candidates are also available on the Resources for drug discovery section of our Elsevier Coronavirus Information Center page. The next step will be screening the literature and narrowing down the list.

I would love to hear your own ideas and thoughts on the next steps! Contact me directly, and let’s discuss.

References

  1. Jernigan DB, CDC COVID-19 Response Team. Update: public health response to the coronavirus disease 2019 outbreak—United States, February 24, 2020. MMWR Morb Mortal Wkly Rep. February 25, 2020 [Accessed February 26, 2020]. http://dx.doi.org/10.15585/mmwr.mm6908e1
  2. Corless V. How known drugs could be applied to the current coronavirus outbreak. Advanced Science News. February 6, 2020 [Accessed February 26, 2020]. https://www.advancedsciencenews.com/how-known-drugs-could-be-applied-to-the-current-coronavirus-outbreak
  3. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. February 3, 2020. [Accessed February 26, 2020]. https://dx.doi.org/10.1038/s41586-020-2012-7
  4. Choi Y, Bowman JW, Jung JU. Autophagy during viral infection-a double-edged sword. Nat Rev Microbiol. 2018;16(6):341-354. https://dx.doi.org/10.1038/s41579-018-0003-6.
  5. Gassen NC, Niemeyer D, Muth D, et al. SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection. Nat Commun. 2019;10(1):5770. https://dx.doi.org/10.1038/s41467-019-13659-4

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