August 10, 2020

Three drug development strategies to combat 2019 novel coronavirus

Three drug development strategies to combat 2019 novel coronavirus

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 three 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 Biomedical 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 121 drugs and biomolecules that were previously described as effective against other coronaviruses, including SARS-CoV. Many of these drug candidates likely hold merit. They were most likely not approved to treat coronavirus infection because the previous coronavirus outbreaks ended before drug candidate testing could be completed.

Feel free to contact me if you would like to get the list of references corresponding to these drugs.

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 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.

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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