List of Antivirals for Enteroviruses: Coxsackievirus B and Echovirus
Here is a list of supplements and drugs that are antiviral for coxsackievirus B and echovirus, two enteroviruses
strongly associated with chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS).
Note though that antiviral effects
in vitro (in cell line tests) may not necessarily translate to effects
in vivo (in the body), when the drug or supplement is taken orally. This is because with in vitro studies, they use a certain concentration of the drug or supplement in a cell line to achieve an antiviral effect. But that concentration may be too high to achieve in the body when the drug or supplement is taken orally.
Dr John Chia has found that the enteroviruses most commonly found as active infections in ME/CFS patients are:
1
- CVB3 and CVB4 first and foremost
- Then less frequently CVB2, EV6, EV7 and EV9; and then much less frequently EV11
Antiviral Drugs for Coxsackievirus B:
interferon alpha (immunomodulatory drug) for CVB3
1
ribavirin (antiviral drug) antiviral for CVB3
1
OSW-1 (saponin) broad-spectrum antiviral for enteroviruses including CVB3, poliovirus, rhinovirus
1
umifenovir (Arbidol, Russian antiviral drug) antiviral for CVB3, CVB5
1 2 and CVB4
1
fluoxetine (antidepressant drug) antiviral for CVB1, CVB2, CVB3
1 2 and CVB4
1
pirlindole (Pyrazidol, MAO-A antidepressant) antiviral for CVB3, and antiviral for other CVBs and echoviruses
1
dipyridamole (vasodilator) broad-spectrum antiviral for picornaviruses including CVB3
1 2
itraconazole (anti-fungal) broad-spectrum antiviral for enteroviruses including CVB3, CVA16, poliovirus, enterovirus-71, enterovirus 68, rhinovirus
1 2
bosentan (pulmonary hypertension drug) antiviral for CVB3 (and likely all CVBs)
1 More info
here.
valsartan (ARB blood pressure drug) antiviral for CVB3 (and likely all CVBs)
1 More info
here.
olmesartan (ARB blood pressure drug) antiviral for CVB3
1
lovastatin (statin drug) antiviral for CVB3
1
mycophenolate (immunosuppressive drug) antiviral for CVB3
1
oseltamivir (Tamiflu, antiviral for influenzavirus) antiviral for CVB3 and CVB4
1 (see Table 1 in the raoulic acid full paper)
amiloride (diuretic drug) antiviral for CVB3
1 2 3 4
arsenic trioxide (leukemia drug) antiviral for CVB3
1 2
glyceryl trinitrate and
isosorbide dinitrate antiviral for CVB3
1
gemcitabine (chemotherapy drug) antiviral for CVB3 and CVB3 replicons (non-cytolytic CVB3)
1
Note that Dr John Chia found that interferon and ribavirin are effective against CVB3 and CVB5 infections, but found these drugs were not effective against CVB4 infections.
1 2
Antiviral Drugs for Echovirus:
ribavirin (antiviral drug) antiviral for EV5, EV11 and EV18
1 2 3
amantadine (antiviral drug) antiviral for EV5 and EV18
1 2
fluoxetine (antidepressant drug) antiviral for EV1, EV9 and EV11
1
itraconazole (anti-fungal) broad-spectrum antiviral for enteroviruses including EV11
1 2
dipyridamole (vasodilator) broad-spectrum antiviral for picornaviruses
1 2
pirlindole (Pyrazidol, MAO-A antidepressant) antiviral for echoviruses
1
Antiviral Supplements for Coxsackievirus B:
dihydroquercetin (DHQ, a flavonoid) is a antiviral (as good as ribavirin) for CVB4.
1 Used by Dr Chia.
Aegle marmelos (bael fruit, bilva) antiviral (as good as ribavirin) for CVB1 to CVB6
1
Emblica officinalis (Phyllanthus emblica, amla) root antiviral for CVB3
1 2
shuang huang lian (Chinese herbal formula) antiviral for CVB3
1 2
garlic antiviral for CVB3
1
curcumin antiviral for CVB3
1
chlorogenic acid (6% in coffee; 50% in green coffee bean) antiviral for CVB3 and CVB5
1 2
baicalein (from Scutellaria baicalensis, Chinese skullcap) antiviral for CVB3
1
Paris polyphylla (Qi Ye Yi Zhi Hua, Chong Lou) antiviral for CVB3 and enterovirus 71
1
raoulic acid (from Raoulia australis) antiviral for CVB3 and CVB4
1
Dodonaea viscosa (hopbush) antiviral for CVB3
1
oroxylin A (from Scutellaria baicalensis) may be antiviral for CVB3
1 and for enterovirus 71
1
oxymatrine (from Sophora flavescens root) immunomodulator for coxsackievirus B
1
ursolic acid antiviral for CVB1 and enterovirus 71
1
apigenin antiviral for CVB1 and enterovirus 71
1
emodin (from Japanese knotweed, aloe vera, rhubarb) antiviral for CVB3, CVB4 and CVB5
1 2 3
Spatholobus suberectus (Ji Xue Teng) antiviral for CVB3 and CVB5
1 2 3 4
Sophora tonkinensis (Shan Dou Gen) antiviral for CVB3 and CVB5
1
Terminalia chebula (haritaki, He Zi) antiviral for CVB3 and CVB5
1
Trichosanthes root (Tian Hua Fen, Chinese cucumber) antiviral for CVB3
1
Rhodiola rosea (golden root) antiviral for CVB3
1
Astragalus membranaceus antiviral for CVB3
1
Bupleurum (Chai Hu) antiviral for CVB1
1
Glycine max (black soybean extract, Dan Dou Chi) antiviral for CVB1
1
DHEA (dehydroepiandrosterone) protective during CVB4 infection
1
5-androstenediol 100 times more protective than DHEA during CVB4 infection
1 2 (
more info)
sodium selenite (a form of selenium) antiviral for CVB5
1
Epimedium (horny goat weed) antiviral for CVB4 and CVB5
1 2 3
acemannan (aloe polymannose from aloe vera leaves) antiviral for CVB3
1
Azadirachta indica (neem leaf) antiviral for CVB1 to CVB6 (but most effective for CVB4)
1
sophoridine (from Sophora flavescens root, Ku Shen) antiviral for CVB3
1 2
oxymatrine (from Sophora flavescens root, Ku Shen) antiviral for CVB3 and immunomodulator for coxsackievirus B
1 2
Isatis tinctoria (dyer’s woad, Da Qing Ye, Ban Lan Gen) antiviral for CVB3
1
Indirubin derivative E804 antiviral for CVB3
1
yakammaoto (Chinese herbal formula) antiviral for CVB4
1
cinnamaldehyde (cinnamon essential oil is about 90% cinnamaldehyde) antiviral for CVB3
1
hyaluronic acid antiviral for CVB5
1
Quassia amara antiviral for CVB2
1
Rheum palmatum root (Chinese rhubarb, Turkish rhubarb) antiviral for CVB3
1
fatty acid synthase inhibitors (these include: amentoflavone, oleic acid, keemun tea, Parasitic loranthus, EGCG) are antiviral for CVB3
1 2
EGCG (from green tea) antiviral for CVB3
1
clinoptilolite (a natural zeolite) antiviral for CVB5
1
selenium deficiency increases virulence of CVB3
1
vitamin E deficiency increases virulence of CVB3
1
copper deficiency increases virulence of CVB3
1
nicotinamide (aka: niacinamide, vitamin B3) antiviral for CVB4 and CVB5
1
ginsenosides antiviral for CVB3
1
wild berry fruit extracts antiviral for CVB1
1
berberine antiviral for CVB3
1
chrysin antiviral for CVB3
1
Re Du Ning antiviral for CVB3
1
Spirulina platensis antiviral for CVB4
1
Houttuynia cordata antiviral for CVB3 and CVB6
1
fucoidan antiviral for CVB4
1
Antiviral Supplements for Echovirus:
shuang huang lian (Chinese herbal formula) antiviral for EV11
1
garlic antiviral for EV11
1
oxymatrine (from Sophora flavescens root) immunomodulator for echovirus
1
betulin and
betulinic acid (from birch bark and Chaga mushroom) antiviral for EV6
1
Spatholobus suberectus Dunn (Ji Xue Teng) antiviral for EV9 and EV29
1 2
Sophora tonkinensis (Shan Dou Gen) antiviral for EV9 and EV29
1
latex from fig fruit (Ficus carica) antiviral for EV11
1
beta-lapachone (from Lapacho) antiviral for EV19
1
clinoptilolite (a natural zeolite) antiviral for EV7
1
lactoferrin antiviral for EV5
1
bismuth salts (such as bismuth subsalicylate) antiviral for EV12
1
Re Du Ning antiviral for EV11
1
serum albumin (of bovine and human origin) antiviral for EV7 and other echoviruses
1
EGCG (from green tea) antiviral for EV11
1
Antivirals for Enteroviruses and Picornaviruses in General:
lamivudine (Epivir) an antiviral used by Dr Chia for enterovirus infections, although he found Epivir is not effective for EV6 and EV7.
1
EGCG (extract from green tea) antiviral for enteroviruses
1
hinokitiol (found in hiba wood essential oil) antiviral for picornaviruses
1
guanidine but very toxic antiviral for picornaviruses
1 2 3
Antiviral Mechanisms:
From the studies referenced above, the following info was extracted:
•
Fluoxetine and its metabolite norfluoxetine markedly reduced the synthesis of coxsackievirus RNA and protein. It might work by targeting the enterovirus 2C protein.
•
Pirlindole inhibits the RNA replication of coxsackieviruses and echoviruses. It likely works by targeting the enterovirus 2C protein. In a
study, pirlindole was specifically shown to inhibit CVB replicons (non-cytolytic viruses).
• Curcumin potently inhibits coxsackievirus replication through dysregulation of the ubiquitin-proteasome system (UPS). Proteasome inhibitors reduce CVB replication via inhibition of viral RNA transcription and protein synthesis.
1
•
Itraconazole (Sporanox) is a broad spectrum anti-enterovirus compound that inhibits viral RNA replication by targeting oxysterol-binding protein.
1
•
OSW-1 is a potent broad spectrum anti-enterovirus compound that inhibits viral RNA replication by targeting oxysterol-binding protein.
1
•
Arbidol (umifenovir) decreased the CVB5 RNA level in infected host cells.
1
• Arbidol inhibits the high expression of IL-10 induced by CVB4; this IL-10 is key to the chronic persistence of CVB4, and Arbidol's IL-10 inhibition helps clear this virus.
1 More info in
this post. Note that the antiviral tenofovir strongly inhibits IL-10.
1
• Ribavirin has a number of antiviral mechanisms, including causing lethal mutagenesis of the viral genome.
1
•
Dipyridamole has little or no antiviral activity, but is capable of remarkably enhancing the antiviral activity of IFN-α.
1
• Spatholobus suberectus extracts have remarkable anti-CVB3 activity in vitro. CVB3 messenger RNA (mRNA) is significantly inhibited by Spatholobus suberectus.
• Trichosanthes kirilowii (the ethyl acetate extract) has a significant protective effect on HeLa cells infected with CVB3 (an in vitro study).
• Aegle marmelos Corr (bael fruit powder, bilva powder) has similar efficacy to ribavirin. Marmelide, from Aegle marmelos Corr, interfered with early events of the replicative cycle like adsorption and penetration.
• Hinokitiol imports zinc ions into the cell, which exerts antiviral effects by interfering with the viral life cycle.
•
Astragalus may inhibit the replication of CVB3 RNA
Note: when a study demonstrates a compound has antiviral efficacy against a specific enterovirus serotype, such as for example CVB3, that is because the study only investigated that particular serotype; but the same compound may potentially also have efficacy against other serotypes (but this is not known for sure).
General Notes:
•
Curcumin has a short half life of 3 to 6 hours, so you need to take curcumin 3 or 4 times a day.
• The anti-enteroviral compound in
Emblica officinalis (amla) is called phyllaemblicin B. A
study on
phyllaemblicin B found it has strong antiviral effects against CVB3.
• The anti-enteroviral compound in
Rhodiola rosea is called salidroside.
• The anti-enteroviral compound in
Epimedium (horny goat weed) is called icariin. The icariin content of horny goat weed around 0% to 2.7%.
1
• The anti-enteroviral compounds in
Sophora flavescens root (Ku Shen) are oxymatrine, matrine and sophoridine. As well as antiviral effects, oxymatrine and matrine also have an immunomodulatory action that can fight enteroviruses.
• The anti-enteroviral compound in
Aegle marmelos Corr is called marmelide. Maximum safe daily dose of Aegle marmelos Corr (bael fruit powder, bilva powder) is 40 grams (this is by my calculations, based on data from the Aegle marmelos study). A
study on the
marmelide component from the herb Aegle marmelos (bael fruit) showed it is more potent than ribavirin against CVB1 to CVB6.
• A
study on
dihydroquercetin (a flavonoid supplement) show it is as strong or stronger than ribavirin in its antiviral effect against CVB4.
• A
study on
curcumin showed it is potently antiviral for CVB3.
• A
study on the medicinal plants
Dodonaea viscosa,
Rumex nervosus and
Rumex abyssinicus found they have strong activity against CVB3.
•
EGCG inhibits folate.
•
Emodin is a laxative.
•
Trichosanthes root is toxic in higher amounts.
•
Sodium selenite (a form of selenium) is not to be confused with sodium selenATE (another form of selenium).
• The Chinese herbal formula
Qi Hong = Astragalus membranaceus + Rhodiola rosea + Sophora flavescens.
• The Chinese herbal formula
Shuang Huang Lian = Lonicera japonica + Scutellaria baicalensis + Fructus Forsythiae + Saccharum. The main antiviral compounds in this formula are forsythoside A, baicalin and chlorogenic acid.
1 2 Note that baicalin is not to be confused with baicalein (both are found in Scutellaria baicalensis). A
study on Shuang Huang Lian found it was more potent than ribavirin.
•
Yakammaoto is a Chinese herbal formula containing 9 ingredients: Ephedra sinica, Pinellia ternate, Zingiber officinale, Tussilago farfara, Aster tataricus, Ziziphus jujube, Belamcanda chinensis, Asarum sieboldii, and Schisandra chinensis.
•
Isatis tinctoria is sometimes also called Isatis indigotica.
•
OSW-1 is a natural compound extracted from the bulbs of the plant Ornithogalum saundersiae that has been studied mainly for its anti-cancer activity.
•
Garlic is best not co-administered with Chinese skullcap.
1
•
Ursolic acid has a poor oral bioavailability of only 0.6%,
1 likely due to being metabolized by the gut wall and liver, as well as being poorly absorbed by the intestine.
1 An apple contains around 50 mg of ursolic acid in the peel.
1 Ursolic acid has been shown to damage DNA (although it also has an anti-cancer action), which is thought may constitute a serious problem.
1
Antivirals Able to Cross the Blood-Brain Barrier:
Since ME/CFS may involve an enteroviral infection within the central nervous system, anti-enteroviral compounds that can penetrate the blood-brain barrier might be of particular benefit. I found studies showing that the following antiviral compounds can cross the blood-brain barrier:
• Fluoxetine crosses the blood-brain barrier, and furthermore fluoxetine concentrates into the brain and central nervous system at levels 20 times higher than in the blood. So low oral doses of 20 to 40 mg of fluoxetine have been shown to produce high concentrations of 14 μM in the brain (much higher than its EC50 concentration of 2.3 μM).
1 However, the antiviral effects of fluoxetine are unfortunately not linearly dose dependent (see Fig 1 of
this study), and it turns out that even a 30 μM concentration provides no more antiviral effect than 2.3 μM.
•
Oseltamivir
•
Dipyridamole
•
Lovastatin
•
Amantadine
• Icariin from Epimedium (horny goat weed) might cross the blood-brain barrier into brain tissues.
1
• Baicalein from Chinese skullcap is able to penetrate the blood-brain barrier.
1
• Indirubin from Isatis tinctoria herb (Da Qing Ye), and from Indigo naturalis powder (Qing Dai), is able to cross the blood-brain barrier.
1
•
Curcumin
•
Chlorogenic acid
Non-Cytolytic Enteroviruses: the Intracellular Side of an Enterovirus Infection:
In chronic infections, enteroviruses such as coxsackievirus B and echovirus can exist in two distinct forms: the regular
lytic form of the virus (comprising viral particles), and a
non-cytolytic form (comprising simply naked viral RNA), which lives inside cells as a chronic, smoldering intracellular infection. It is thought that as well as the lytic form, the non-cytolytic form of enterovirus may also play causal role in ME/CFS.
1
Since non-cytolytic enteroviruses comprise naked enteroviral RNA rather than the more usual viral particles, antivirals which work by viral particle entry inhibition or uncoating inhibition mechanisms will not have any direct effect on non-cytolytic enterovirus infections.
However, I believe that viral genome replication inhibitor antivirals will work for both lytic and non-cytolytic enteroviruses. And any antiviral that increases interferon alpha will I think fight non-cytolytic enteroviruses, because interferon alpha activates the intracellular immune response which targets such non-cytolytic infections.
In a
study, pirlindole was specifically shown to inhibit CVB replicons (non-cytolytic viruses).
More information about non-cytolytic enteroviruses is given
here.
Non-cytolytic enteroviruses are also known as: non-cytopathic enteroviruses, terminally-deleted enteroviruses, defective enteroviruses, defective interfering enteroviruses and replicons.
EC50 Values of Antivirals:
When measuring the potency of an antiviral through in vitro experiments in cells lines, the EC50 (effective concentration) test is often used. The EC50 is the concentration of an antiviral compound in solution that will lead to a 50% reduction in viral replication in the cell line. The IC50 (inhibitory concentration) in the context of antivirals I believe is the same as EC50.
The EC50 is typically expressed in micrograms of the antiviral compound per milliliter of solution (μg/ml), or alternatively expressed in micromoles (μM). (To convert μM to μg/ml, multiply by the molecular weight, and divide by 1000).
Below are some EC50 figures for various antivirals tested in vitro. Note that the lower the EC50 figure, the stronger the antiviral.
The actual usefulness of an antiviral compound depends on its
therapeutic index (aka: selectivity index), which is equal to the ratio: CC50 / EC50. Here, the CC50 is the cytotoxic concentration — the concentration of the antiviral that kills 50% of the cells in the cell line. For a useful antiviral, you obviously want the CC50 concentration to be quite a bit higher than the EC50.
EC50 Values for Antivirals (values shown in bold, and expressed as μg/ml). Note that smaller values represent a more potent antiviral:
Arbidol:
HEp-2 cells: CVB3 =
13.1,
HEp-2 cells: CVB5 =
6.6 1 2
Oseltamivir (Tamiflu):
Vero cells: CVB3 =
6.8, CVB4 =
18 1
Raoulic acid:
Vero cells: CVB3 =
0.33, CVB4 =
0.40 1
Ribavirin:
HeLa cells: CVB3 =
1.9,
Vero cells: EV5 =
22, EV18 =
7.6 1 2 3
Amantadine:
Vero cells: EV5 =
1.0, EV18 =
5.0 1 2
Phyllaemblicin B (from Emblica officinalis):
HeLa cells: CVB3 =
7.8 1
Marmelide (from Aegle marmelos):
Vero cells: CVB1 to CVB6 =
63 (by comparison, study found ribavirin IC50 =
2000)
1
OSW-1:
BGM cells: CVB3 =
0.002 1
Paris polyphylla extract:
HeLa cells: CVB3 =
157 (by comparison, study found ribavirin IC50 =
129)
1
Baicalein (from skullcap herb):
BGMK cells: CVB3 =
7.8 and SI =
34 (by comparison, study found ribavirin IC50 =
16 and SI = 15)
1
Ursolic acid:
BCC-1/KMC cells: CVB1 =
0.4 (SI = 251); enterovirus 71 =
0.5 (SI = 201)
1
Indirubin derivative E804: and
Akt Inhibitor IV:
HeLa cells: 25 μM led to 2 log reduction in CVB3
1
Platelet-derived growth factor receptor tyrosine kinase inhibitor III (E5(1)):
HeLa cells: 25 μM led to 4 log reduction in CVB3
1
Anti-Enteroviral Drugs in the Research Pipeline:
The following pharmaceuticals have shown anti-enterovirus or anti-picornavirus activity, and are currently under research, but are not as yet available.
TTP 8307 — potently inhibits CVB3 and poliovirus by interfering with the synthesis of viral RNA
V-073 / SCH-48973 (pocapavir) — capsid inhibitor for poliovirus, CVB and echovirus
GPC-N114 — RNA polymerase inhibitor, broad-spectrum anti-enterovirus, potent for CVB3 in vitro
Ro 09-0179 — flavone from Agastache rugosa, antiviral for rhinoviruses and CVB
SDZ 35-682 — a capsid-binding agent, potently inhibits several rhinoviruses and EV9
MDL-860 — broad-spectrum anti-picornavirus activity, including CVB3
TBZE-029 — inhibits CVB3, EV9, CVA9 and enterovirus 68
AG-7088 (rupintrivir) — rhinovirus protease inhibitor
R77975 (pirodavir) — rhinovirus inhibitor
LY-122772 (enviroxime) — rhinovirus and enterovirus inhibitor
WIN 63843 (pleconaril, Picovir) — a capsid-binding agent for rhinovirus and enterovirus
WIN 51711 (disoxaril) — rhinovirus and enterovirus inhibitor
T-705 (favipiravir, Avigan) — RNA polymerase inhibitor, antiviral for poliovirus and rhinovirus
BTA-798 (vapendavir) — inhibits rhinovirus
Rega Compound 17 — inhibits in vitro replication of CVB3, CVB4, CVB5 and CVB6
Rega Compound A — completely eradicates CVB4 from the tissues and organs of mice
1