For the tl;dr, scroll to the bottom.
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So with the coronavirus pandemic going on, like everyone else I've been stuck home with little more to do outside of work than to read up on this beast with the minor privilege of being able to ask friends who are more competent in such matters than me about it. When I see friends and family in my hometown of San Francisco who work in ER wards and nearby county clinics posting their stories and PPE fundraisers on Facebook, I know that something is very wrong, and so in spite of my lay credentials ( I failed chemistry my first semester in university, only to pass within an inch of my life the 2nd semester), feel compelled to post what I've learned about it.
I'm going to describe by way of outlining my learning progression, because I want it to be clear how I got from A to B to C.
As the epidemic in China was starting to wane, but picking up elsewhere, my anxiety grew. Seeing reports that an HIV antiviral Kaletra (lopinivir and ritonavir) was showing early anecdotal success in patients in China, I asked my Chinese b-school classmates for links to scholarly papers gaining currency on the topic in China, simply so that I could try to reduce my anxiety.
One of the papers they identified was this, a preprint from Hong Kong Polytechnic University cleverly using Python tools and a drug database to do a drug-docking study:
In-silico drug screening against SARS-nCoV-2:
https://f1000research.com/articles/9-129
I remembered from a UCSF biotech researcher I roomed with two decades ago that proteins are capable of interacting if they have a 3D structural match and complementary chemical bonds at their active sites - like two puzzle pieces fitting together - so I appreciated the approach and marveled how far the technology had come in 20 years that anyone with Python could do such simulations. These simulations are called 'in silico', to distinguish themselves from 'in vitro' (testing a compound on actual animal cells, typically in a petri dish), and 'in vivo', (testing the efficacy of a compound in a live animal or even a live human population).
Reading that paper sensitized me to the proteins that are being targeted by drug designers during this epidemic. For example, there is the protein that makes the virus's spikes. There are other proteins required for the virus to enter a cell and begin replicating itself using the cell's machinery. Altogether there are some 20-30 unique proteins that make up this coronavirus, which is technically called SARS-CoV-2. (Side note: A lot of papers out of China were calling the virus 2019-nCoV, so make sure to use that keyword if you ever want to research papers out of China especially from the early period of the pandemic).
The protein the researchers from Hong Kong Polytechnical University were targeting is called 3CLpro. They usefully compare it to the coronavirus from the 2003 outbreak:
" All 11 3CLpro sites2 are highly conserved or identical (Extended data7, Table S1), inferring that their respective proteases have very similar specificities. The 3CLpro sequence of SARS-CoV-2 has only 12 out of 306 residues different from that of SARS-CoV (identity = 96%)."
They map the 'in silico' efficacy of FDA-approved prescription drugs, and they also study other non-prescription compounds that are typically plant-derived. They use the binding energy as the figure of merit for the efficacy of a drug or compound to affect the 3CLpro protein. The logic goes, if you can bind most strongly to one of the virus' protein sites, then you're probably inhibiting the virus' performance somewhat.
Since I could see there was already a lot of scholarly work happening on the approved presription antivirals, such as lopinivir/ritonavir and remdesivir, I began searching on 3CLpro with regards to the non-prescription compounds that ranked quite highly in the HK Polytechnic U researchers' study -specifically hesperidin and diosmin. Hesperidin and diosmin are found prevalently in orange peels and orange juice, and hesperidin is also found prevalently in peppermint.
On performing the search, one of the earliest hits was this:
https://www.sciencedirect.com/science/article/pii/S0166354205001257
which is a 2005 paper out of China Medical University in Taiwan covering in-vitro drug testing on SARS-nCoV using Vero cells.
This 2005 paper performed in the wake of the original SARS epidemic describes the compounds they tested against the 3CLpro protein in a type of standard animal cell test called "Vero" cells. (These are cells that come from African Green Monkeys, and have been used since the 1950's as a standard cell test that researchers could easily replicate findings against)
The 2005 Taiwan paper also tests compounds that the HKPU study didn't even look at, like Indigo and Sinigrin. Evidently they didn't even have the benefit of in silico screenings, as their motivation for testing these choices of compounds was based on:
"Isatis indigotica root and phenolic Chinese herbs were frequently used for the prevention of SARS during the SARS outbreaks in China, Hong Kong, and Taiwan" and "In addition, several herb-derived phenolics aloeemodin, hesperetin, quercetin, and naringenin have been accredited with antiviral effects against poliovirus, vesicular stomatitis virus, Sindbis virus, herpes simplex virus types 1 and 2, parainfluenza virus, and vaccinia virus" (with trailing citations)
As the authors acknowledge, it turns out that hespiritin performs well in inhibiting 3CLpro's cleaving action, which is otherwise necessary for the virus to propagate, at relatively low concentrations compared with the other compounds, at 8 micrograms per mL.
Finally, and usefully, the Taiwanese researchers looked at what upper limit of quantity of the compounds under test would actually kill the test cells. Lots of compounds kill viruses in a petri dish, but you want to know which of those compounds doesn't also kill the cells they are intended to protect. As they say after all, "the dose makes the poison."
So hespiritin starts to look interesting, but so does sinigrin, because ostensibly it is so benign to the test cells that it is beyond the top of their scale in terms of ability to harm the cells. Sinigrin is common in many green vegetables such as brussels sprouts and collard greens. It's also what gives horseradish its unique test.
Also at this point, note the slightly different spelling hesperidin -> hesperitin. This will become relevant later, but essentially hesperidin is the naturally-occurring compound, and hesperitin is what the human body metabolizes hesperidin into.
So I started to think about possible administration routes of these compounds. The two that stand out are 1) ingestion, because it's the easiest and most popular form of taking medication, and 2) (since this manifests as a respiratory and pulmonary infection . . . inhalation.
But then I felt stuck. Things are looking up, but I don't know what to do next, or even if my approach to reviewing the research is valid. On the advice of a friend who has a PhD in Systems Biology and practicing in the pharmaceutical industry, he suggested I look up the safety of these administration methods with regards to these compounds.
After a lot of cited online research later, I learned that Sinigrin all-too-easily becomes poisonous at high ingestion (and inhalation (!) ) doses! Anyone who's ever taken a deep whiff of horseradish or sushi wasabi can speak to this. So this literature review helpfully enabled ruling it out, leaving Hesperidin as the only remaining candidate to show high in vitro efficacy at accessibly low concentrations.
Then we naturally want to learn how can this compound be had in therapeutically effective doses? For this I did a bit of math based on the Taiwan paper. The Taiwan researchers identify the effective concentration for hesperidine to be 2.5 micrograms (mcg or μg) per mL (presumably aqueous). Taking simple orange juice as the most available vessel for this, and treating the human body as having the same density as water (1 kg per litre) and assuming uniform concentration of the ingested compound in the body, then a 100-kg person, (say a heavier male) would need 250000 μg, or 250 mg, of hesperidine maintained over some period relevant to the virus' generation cycle.
According to this really helpful database of concentrations of various compounds in foods, we find that production orange juice contains 26 milligrams / 100ml of hesperidin. Hesperitin is about half the molar weight of hesperidin, so we need to treat this as an effective 13 milligrams / 100ml of hesperitin. So how much OJ does a 100-kg person have to retain without excreting any through urine, in order to reach the dose level indicated by the Taiwan study? The simple math answer is 1.9 litres. The average human's weight, 62-kg, would need about 1.2 litres.
While there are many questions remaining that, absent further expert advice, could affect the efficacy of orange juice on either prophylactically protecting against a coronavirus infection, or tamping down a nascent existing infection, considering the universally-accepted safety of orange juice consumption in the world, the choice to drink orange juice is essentially a zero-cost option. It doesn't pose a health-risk anywhere close to these quantities (the equivalent of having passed phase-1 clinical trials for pharmaceutical drugs), its cheap for developed country consumers, and its widely available, and in all likelihood is sitting inside your fridge as I write.
Don't like drinking all that orange juice? Well hesperidine (paired with diosmin, which is anyway also naturally prevalent in the same orange juice) is manufactured in pill form, with the hesperidine component typically dosed at 100 mg a day. In the US, while they can't be advertised for treatment of a disease, instead the FDA regards these constituent compounds as GRAS ("Generally Regarded As Safe") via FDA's published GRAS certifications on Orange Pomace and Orange Extract.
That was all regarding the oral ingestion route. The inhalation route, of course, should be of particular interest for acute cases, but the downside risk is just this side of dicey that I'd prefer not to speculate on a public forum about it; suffice to say that if this OJ oral ingestion is found to have merit, I'd be happy to share with medical professionals the learnings I've assembled so far on the inhalation route. (Suffice to say that it doesn't involve orange juice).
So I close with a request: If you've gotten this far, I would really appreciate if you can poke holes in this analysis, and to particularly include same in the comments below so that others can evaluate. In particular, I'd love a qualified answer to the question, "If these are qualified research paths, then which researchers are in the process of studying them?"
Please consider yourself warmly-welcomed to troll, call me a snake-oil peddler, or whatever, but just put some reasoning behind your concerns so that the reasoning can be shored up or thrown out as appropriate. Disclaimer that I have no financial interest in any company, venture, or trading position associated with the above - I just want to get back to normal-life again.
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tl;dr
Drink extra orange juice. And don't gain a false sense of security from doing so.
Update 2 April: I 'professionalized' up this post into a Medium post that I'm feeling relieved has been getting attention from appropriate places:
https://medium.com/@ricksher/with-the-coronavirus-epidemic-still-reaching-its-zenith-in-the-us-i-observe-friends-and-family-in-bff0e873fb5
