Research & News RoundUp
We’re keeping an eye on the latest peer-reviewed and pre-print publications to see what natural compounds are surfacing with promising anti-coronavirus activity. Even as the number of cases and death toll continues to grow, we think these are interesting contenders for limiting the effects of COVID-19.
This was a rewarding undertaking for a couple of reasons- I have a strong respect for the power of flavonoids and have published on them previously (see this peer reviewed pub on detox modulators and our work on uncovering methylation adaptogens). Even if these compounds eventually prove insufficient against COVID-19 targets, many are found in fruit and vegetables consumed in a healthy diet and are beneficial for other reasons. We can start eating these today. Finally, some of these compounds are already in clinical trials! Read about quercitin’s here. And finally, we are excited about the swaths of collaborative and rapid science being release on COVID-19, and to be able to share it with you.
A note about molecular docking studies: This is a common strategy used to screen for drugs and other molecules that may have favorable effects on any given target. They use high-throughput screening to scan vast databases of known interactions. Scroll down to the appendix below to learn about the specific molecular targets referred to in these tables.
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Citrus
The compounds in this table are all found in citrus foods, especially in the peel, including oranges, lemons, limes and grapefruit.
| Compound | Target | Reference |
| Naringenin | COVID main protease Mpro binding | In vitro docking study (preprint) |
| Hesperidin | Targets interface between Spike and ACE2
ACE2 binding 3CLpro binding |
Database of molecular binding studies Ref |
| Hesperidin | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
| Hesperetin | Ppro binding | Database of molecular binding studies Ref |
| Hesperetin | ACE2 inhibitor | In vitro study |
| Hesperetin | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding Inhibits 3C-like protease (3CLpro). |
In vitro docking study (preprint) |
| Neohesperidin | Ppro binding | Database of molecular binding studies Ref. |
| Neohesperidin | 3CLpro binding
ACE2 binding |
Database of molecular binding studies Ref |
| α-glucosyl hesperidin | Helicase (Nsp13) inhibitor | Database of molecular binding studies Ref |
| Naringenin | ACE2 inhibitor | In vitro study |
| Naringenin | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
| Tangeretin | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
| Nobiletin | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
From this In vitro docking study (preprint): “Interestingly, we found that citrus and galangal compounds performed superior binding affinities to each receptor compared to those of the compounds of Curcuma sp. and sappan wood. These higher binding affinities of those of compounds could be represent significantly of its stronger inhibitory activities to the viral infection.”
Update April 20 2020:
Since this article was published, two more preprint articles have become available, both with promising findings of the potential mechanism of citrus derivatives, as well as epigallocatechin gallate, mentioned next:
From this article: “The results showed that hesperidine, cannabinoids, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and cannabinoids had about the same pose as nelfinavir, but were better than chloroquine and hydroxychloroquine sulfate as Mpro inhibitors. These plant compounds have the potential to be developed as specific therapeutic agents against COVID-19.”
From this article: “Based on recent computational and experimental studies, hesperidin, a bioactive flavonoid abundant in citrus peel, stands out for its high binding affinity to the main cellular receptors of SARS-CoV-2, outperforming drugs already recommended for clinical trials. Thus, it is very promising for prophylaxis and treatment of COVID-19, along with other coexistent flavonoids such as naringin, which could help restraining the pro-inflammatory overreaction of the immune system.”
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Tea (Camellia Sinensis)
While green tea is considered to have the highest concentrations of many of the following flavonoid compounds, they are also found in white, yellow, oolong, black and fermented teas, which are all made from the plant Camellia sinensis.
| Compound | Target | Reference | ||
| Catechin | 3CLpro binding | In vitro docking study (preprint) | ||
| Epicatechin | ACE2 inhibitor | In vitro study | ||
| Epicatechin-gallate | 3CLpro binding | In vitro docking study (preprint) | ||
| Epigallocatechin gallate (EGCG) | Ppro binding | Database of molecular binding studies Ref | ||
| Theaflavin 3,3′-di-O-gallate | 3CLpro binding | Database of molecular binding studies Ref | ||
| Theaflavin 3,3′-di-O-gallate | RdRp binding and potential inhibition | Database of molecular binding studies Ref | ||
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Chinese Skullcap (Scutellaria baicalensis)
The following compounds are found in Chinese Skullcap. Note that while some of these compounds are found too in American Skullcap (Scutellaria lateriflora), their quantity is much less. These herbs are generally not considered interchangeable.
| Compound | Target | Reference |
| Baicalin | Ppro binding
RdRp binding and potential inhibition |
Database of molecular binding studies Ref |
| Baicalin | ACE2 receptor binding | In vitro docking study (preprint) |
| Baicalin | Inhibitor of pro protein convertase furin (furin cleavage) | In vitro study |
| Chrysin | Ppro binding | Database of molecular binding studies Ref |
| Chrysin | Inhibitor of pro protein convertase furin (furin cleavage) | In vitro study |
| Chrysin-7-O-beta-glucuronide | 3CLpro binding | Database of molecular binding studies Ref |
| Cosmosiin | 3CLpro binding | Database of molecular binding studies Ref |
| Wogonoside | Coronavirus virulence factor (Nsp1, Nsp3c, ORF7a) binding | In vitro docking study (preprint) |
Read about potential drug interactions with Chinese Skullcap and more here.
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Andrographis (Andrographis paniculata)
Andrographis is another plant native to the Asian continent. It has a history of traditional use for infections, including viral infections with some evidence to support its use also.
| Compound | Target | Reference |
| (S)-(1S,2R,4aS,5R,8aS)-1-Formamido-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl-2-amino-3-phenylpropanoate | Ppro binding
3CLpro binding |
Database of molecular binding studies Ref |
| (1S,2R,4aS,5R,8aS)-1-Formamido-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl 5-((R)-1,2-dithiolan-3-yl) pentanoate | 3CLpro binding
RdRp binding and potential inhibition |
Database of molecular binding studies Ref |
| Andrographiside | 3CLpro binding
RdRp binding and potential inhibition |
Database of molecular binding studies Ref |
| (1S,2R,4aS,5R,8aS)-1-Formamido-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl 2-nitrobenzoate | 3CLpro binding | Database of molecular binding studies Ref |
| Andrograpanin | 3CLpro binding | Database of molecular binding studies Ref |
| 2-((1R,5R,6R,8aS)-6-Hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl benzoate | 3CLpro binding
RdRp binding and potential inhibition |
Database of molecular binding studies Ref |
| 14-Deoxy-11,12-didehydroandrographolide | RdRp binding and potential inhibition | Database of molecular binding studies Ref |
| (R)-((1R,5aS,6R,9aS)-1,5a-Dimethyl-7-methylene-3-oxo-6-((E)-2-(2-oxo-2,5- dihydrofuran-3-yl)ethenyl)decahydro-1H-benzo[c]azepin-1-yl)methyl 2-amino-3-phenylpropanoate | RdRp binding and potential inhibition | Database of molecular binding studies Ref |
| Andrographolide | RdRp binding and potential inhibition | In vitro docking study (preprint) |
See here for safety and interaction information about Andrographis.
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Turmeric
The following compounds are curcumin and curcurmin-derived products that confer the bright yellow pigment to turmeric.
| Curcumin | 3CLpro binding
Spike protein binding ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
| Demethoxycurcumin | 3CLpro binding | In vitro docking study (preprint) |
| DMC | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
| BDMC | Spike protein binding
ACE2 binding SARS-CoV-2 protease binding |
In vitro docking study (preprint) |
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Quercetin
Quercetin is a polyphenol found in several plant foods, especially apples, red onions, capers, fennel leaves, kale, broccoli, and green tea.
| Quercetin | 3CLpro binding
RdRp binding and potential inhibition ACE inhibitor |
In vitro docking study (preprint) |
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Luteolin
Luteolin is found in modest amounts in several foods including celery, thyme, green peppers and chamomile tea. Mexican oregano (different to ‘regular’ oregano) and celery seeds are especially rich sources.
| Luteolin | ACE inhibitor
Inhibitor of pro protein convertase furin (furin cleavage), studied in Dengue fever |
In vitro study |
| Luteolin-7-glucoside | COVID main protease Mpro binding | In vitro docking study (preprint) |
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Rosemary
Rosmarinic acid is a primary active component of rosemary. It is also found in other herbs including peppermint, spearmint, thyme, sage and oregano.
| Rosmarinic acid | Ppro binding
3CLpro binding |
Database of molecular binding studies Ref |
Of course, none of these are proven. Nothing is at this point. Nor can they replace good medical care. Yet at the end of the day, this situation, in the absence of vaccine or medicinal cure, comes down to human vs virus. The strongest wins. The question is, how do we make ourselves stronger? And how can we make the virus weaker? Those are the questions we’ve been looking at answering, even if those answers are tentative.
Check out our related content on our COVID-19 page.
Appendix: Explanation of biological targets
- ACE2 receptor. This is a receptor on human cells that is found in especially high numbers in lung, heart, kidney and in the gastrointestinal tract. More recently, ACE2 receptors have been found to exist in the nasal passages, too, offering an explanation as to how the virus is able to latch on initially and spread down to the lungs and other organs. ACE2 receptors are considered a significant potential target for anti-coronavirus drug development.
- Spike protein. The spike protein promotes attachment between the virus and human cells via the human ACE2 receptor. The current SARS-CoV2 spike protein is understood to have a higher binding affinity to ACE2 receptors than SARS-CoV1, which partly explains its increased rate of infectivity and human-to-human transmission.
- COVID-19 main protease (Mpro).
- Papain-like proteinase (PLpro). PLpro is an indispensable enzyme in the process of coronavirus replication and infection. PLpro is responsible for cleaving the N-terminus of the replicase poly-protein.
- 3C-like main protease (3CLpro). Closely linked with PLpro, 3CLpro (aka Nsp5) cleaves polyproteins to produce mature, functioning enzymes that are essential for the survival of the virus.
- RNA-dependent RNA polymerase (RdRp). Coronaviruses have a specific RdRp called Nsp12, a vital enzyme used for viral replication and transcription.
- Helicase. Helicase is an multi-functional protein that can unravel human DNA strands to allow viral replication to occur. It is not specific to coronavirus.
6 Comments
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I don’t know if I’m not interpreting the names correctly (it’s medical talk after all lol), but I don’t see Vitamin C among the compounds in citrus, even though some studies have shown promise in its ability to limit the effects of coronavirus- see: https://nypost.com/2020/03/24/new-york-hospitals-treating-coronavirus-patients-with-vitamin-c/
Vitamin C found in natural products works fine, but if you want to have a higher dose, a highly reputed practice can provide you with .
Stay tuned, Dean. We will release a vitamin C post soon. We are pretty excited about its use in the ICU and the research being undertaken. Vit C isn’t a flavonoid, so its not included in this blog. DrKF
How does this fit in with these 3 publications?
In silico screening of Chinese herbal medicines with the potential to
directly inhibit 2019 novel coronavirus
A potential role for Galectin-3 inhibitors in
the treatment of COVID-19
Molecular Basis for Treating COVID-19 with Official
Chinese Herbal Formula LCTE
Fred,
There are quite a few botanicals and botanical combinations worth considering for SARS CoV-2. There is quite a bit of research on combination products for SARS CoV-1 as well as preliminary research for CoV-2 (as you list above). Consider listening to my podcast with Dr. John Chen- it’s a really interesting and useful tour of the science (along with traditional history) of Traditional Chinese Medicine. I also have a blog on TCM considerations that might be of interest to you. DrKF
Why is Fisetin not mentioned in this list? From what I have read it is often found to be more effective than other flavonoids.
Hi there. Great point – the science on this topic was rapidly evolving around the time (and still is), so we did our best to choose the most promising compounds based on research available at the time.