Potential Protective Agents (Part 2)
When trying to edit my previous post, I somehow crashed it. It can no longer be commented on. I will continue my thoughts here.
The evidence is strong that SARS-CoV-2 viruses are very similar to SARS-CoV-1 regarding their cell entry and hence proliferation mechanism . The best way to treat acute virus infections is the inhibition of their proliferation by preventing activation or cell access (i.e., virostatic). There are various inhibitors in clinical pipelines targeting the protease and polymerase that are required for the activation or proliferation of the virus. Meanwhile, protease inhibitors have not turned out to be successful in the hospital setting . Nevertheless, the question remains what people could try in order to substantially reduce proliferation in their system and thereby severe symptoms, and an infection of others. Assuming that the overall cell entry mechanism of SARS-CoV-1 and SARS-CoV-2 are the same, including the granular docking process to ACE2 receptors, I suggest checking already researched treatment options for SARS-CoV-1 and other similar coronaviruses (1) that can safely be accessed, (2) that have little risks and side effects, (3) and that can be used before the infection occurs or during the incubation phase.
Your reviews and opinions are welcome.
There is another preprint that I found interesting . The authors argue in their survey that ATP and NADP depletion play a larger role in the fatality course.
Remember, fatality in the hospital setting doesn’t primarily originate from ARDS. That is because ventilators can effectively keep the fluids out of the lungs in most cases. I haven’t heard any clinician saying that they wouldn’t need ventilators because the patients would die anyway. Most of the ventilated patients die indeed but due to other causes, e.g., organ failure, heart failure, nervous side effects, metabolic shock, etc. I remember an interview on Channel 4 News where the doctor said all of his deceased ventilated patients died from a heart attack. Another one on YT said they would advise against reviving heart attacks because it’s painful, takes a lot of personnel and has very little success chances in COVID-19. So my impression is that the lungs are the entry door for the virus. If it gets there from the bronchi, it will affect the whole body nonetheless.
To get back to the referenced paper. The authors include some of the arguments regarding MAPK signaling, nitrosative stress, and cytokines that I made here as well. But what stands out in their work is that they explain another way in that ROS-mediated stress causes a damage factor. ROS causes DNA damage which is repaired by different pathways, including PARP-1. PARP-1 depletes NADP and ATP. NADP is also required for other antioxidative processes to compensate for virus damage. Moreover, the Coronavirus family encode proteins that are able to suppress PARPs, probably by hydrolyzation of ADP-ribose (i.e., PARG) from other proteins . That leads to an overdemand of PARPs to compensate for the ADP loss. Furthermore, there is an oversupply of the ADP-ribose. The study’s authors suspect that this will hence lead to a TRPM2 overactivation and that this overactivation will cause excessive release of Ca2+. That’s why they figure that PARP, PARG, and TRPM2 inhibitors could turn out to be therapeutic agents. However, I don’t think that pan-PARP inhibition is beneficial since other PARPs have antiviral properties. PARP-13 is a zinc-mediated intracellular inhibitor of viral proteins.
The total depletion of NADP will cause a variety of fatal factors. So this should be prevented. Nicotinamide Riboside (NR) could be used to compensate for the depletion. Hydroxychloroquine reduces NADPH oxidase, thereby inhibits the negative outcome of the reduced buffer a little bit. It’s controversial though if pretreatment of either agent has a positive effect.
TRMP2 also interacts with the NLRP3 that the virus activates via another pathway . The release Ca2+ activates NLRP3. The referenced study also showed that stress-induced inhibition of TRMP2 via NAC treatment can lower ROS production and NADPH oxidase activity in a diabetes mouse model. Curcumin is another inhibitor of H2O2-induced TRMP2 signaling . I guess any antioxidative treatment will work.
ATP is important for muscle function (including the heart muscle) and the metabolism. It’s unclear though if a moderate reduction of ATP levels has pathological or physiological meaning because low ATP levels also lead to lower PARG/TRMP2 in the end. The study references NAC as a PARP-1 inhibitor and Tannins as PARG inhibitors . Another study that I found determined (Methyl-)Xanthine as another potent PARG inhibitor . Methylxanthine is contained in cacao, caffeine, and tea products . Regardless of PARG inhibition, ROS again plays a central role in the mediation of SARS-CoV-2 pathology.
Recent study :
Does it teach us anything else than what we already knew?
This survey is more about Vitamine D than about SARS-CoV-2. It’s also received funding from a Vitamine D supplement company. It doesn’t really introduce a pathological mechanism but it’s connecting statistical dots and correlations to point into the direction that Vitamine D deficiency is a risk factor. It’s difficult to neglect all these correlations.
But what I still find baffling is how high the CFR seems to be in the Afro-American population. There is no doubt that limited health insurance is contributing to that ratio but I doubt that this will be the only factor. The study also references this concern for pneumonia cases between 1900 and 1948 . This seems to agree with the new data from the US . The darker the skin, the more sunlight is required for Vitamine D synthesis . That might also be the reason why “hot areas” of the world aren’t safe from the virus. It’s usually where ethnicities with darker skins live, so they would need even more sunlight to have the same Vitamine D levels.
I still see a moderate chance that increased sun exposure will reduce fatality numbers during the summer. Early spring just doesn’t have sufficient UV radiation in many western areas of the world . We would see the first significant decline during May. But due to the current measures, we will see a decline until then anyways. To really prove the hypothesis, they would have to create a complex model that considers sun exposure, self-isolation measures that prevent sun exposure, and skin pigmentation rate in different spots on the world.
The symptom scores and CFR would decrease in April/May then but that also means that the R0 will inversely correlate. That would accelerate herd immunity buildup but also the total number of severe cases, even though the relative number might decrease moderately. If we could achieve herd immunity in the healthy population until next winter, the problem would be solved. If we don’t, we might face another wave in the next winter. All of this consideration is based on the assumption that Vitamine D in fact plays such a significant role, of course.
Do we have a ace in the hole ?…
Green tea rocks!
EDIT: My posts keep disappearing after editing. I guess that the duplication checker filters them out for some reason. Here is the repost:
Thanks, Sorin. This is the third article that points towards green tea. Its discussion as an antiviral isn’t new .
- EGCG is a potent chymotrypsin-like but not trypsin-like proteasome inhibitor . It’s possible that it also inhibits TMPRSS2 but I couldn’t find any evidence.
- EGCGs’ effects on ROS levels are biphasic  . It shouldn’t be considered for that use case because dose absorption can’t be controlled when supplementing. Dose dependency would be preferential.
- EGCG can indirectly inhibit ACE activity . You know the mechanism from other ARBs. It’s still unclear if ARBs are helpful or counterproductive in SARS-CoV-2 infections and in which subgroup or which phase of the infection. Interestingly, Vitamine C suppresses the ACE-inhibitory effect of EGCG. A similar phenomenon, i.e. a suppression of EGCG’s inhibition induced by another antioxidant, has been shown for the ROS levels mentioned before. My guess is that this effect is based on the same mechanism and hence biphasic as well.
- EGCG seems to inhibit Erk/JNK/AP-1/MAPK signaling but in an insignificant degree for MAPK . There is also evidence that EGCG activates p38 MAPK  . Since ROS induces p38 MAPK activation, maybe that’s also due to the biphasic effect?
- The biphasic effect prevents a complete comparative view on the subsequent pathways. They would have to use the same models and dosages, so I’ll spare further research regarding cytokines.
- As Sorin referenced, EGCG could also have a significant effect on the virus’s molecular binding affinity and thereby decelerate proliferation .
- If and how EGCG can enhance zinc ionophore activity seems to be controversial   . It might be similar to Quercetin in that it requires a phytosome or liposome delivery system. Simple green tea won’t work in that case.
- As mentioned before, green tea (not EGCG per se) can also be a potent PARG inhibitor .
Unfortunately, there isn’t sufficient data to differentiate the effect of EGCG depending on the dosage and delivery form. It’s key potential clearly is in the inhibition of the proliferation mechanism of SARS-CoV-2. Inferring from what is known for its ionophore effect, I guess that a liposomal delivery is preferential.
Previously I mentioned how I think that beyond the cytokine storm and the viral proliferation mechanism, the key to a healthy immune response against SARS-CoV-2 must be related to the T cells. Even given decelerated virus proliferation and inhibited cytokine expression, if there is no adequate immune response, there will be a certain point in which the whole metabolism tips over because too many cells are infected or because the virus has reached the heart via its way through the lungs and the epithelium. A new in vitro study verifies that SARS-CoV-2 can, in fact, infect and destroy T lymphocytes, not just ACE2-expressing cells . In order to reduce fatality risk, the inhibition of the virus’s ability to enter these T cells could be the key so that it symptomatically doesn’t differ from common cold coronaviruses anymore.
One of the pathways that are considered as a T cell entry path for SARS-CoV-2 is the CD147 protein. Besides in lymphocytes, CD147 also is prevalent in various epithelial, neuronal, and myeloid cells . That might be the reason that the virus can also induce neuronal damage .
Epithelial cells have both, a high ACE2 and CD147 expression. Both entry paths have to be blocked so that the virus doesn’t reach the heart, i.e., the primary mediator of COVID-19 deaths as it seems (if ventilation support is granted). There are more and more reports of people dying at home or very abruptly even though they didn’t show severe respiratory issues   . No treatment will help if it reaches the heart and people don’t even necessarily notice it until it is too late.
As mentioned before, I don’t expect a single drug to fix all the mechanisms that the virus encodes. It’s even possible that there are multiple antibody types necessary to completely shut the infection process down. All of these antibodies would have to be determined before antibody tests roll out. Besides the whole ACE2 entry suppression topic, early response about a CD147 antibody (i.e., Meplazumab) as add-on therapy seems to be promising . When compared to other treatments such as Hydroxychloroquine, the risks of Meplazumab are limited, which makes its use as a secondary agent straight-forward. Berberine is a natural supplement that could decrease CD147 expression .
It seems as if SARS-CoV-2 uses Cyclophilins A (CypA) and B (CypB) for CD147-channeled cell entry  . Another study tried to elaborate on the interplay of CD147 and CypA/B . CypA induces CD147-mediated ERK activation, which is also induced via the ACE2/ROS/MAPK pathway. CypB induces a Ca2+ flux and a neutrophil response, which is also induced by the TRPM2 pathway. So there are two pathways that are “double-stimulated” by SARS-CoV-2 in the endothelium.
Another interplay is on the ANG2/ROS pathway. SARS-CoV-2 induces ANG2-mediated ROS release. ROS enhances the acetylation of CypA . This acetylated AcK-CypA then mediates endothelial cell dysfunction and monocyte adhesion.
The first studies tried to target CypA/B with Cyclosporin A (CsA). Another inhibitor MM284 has been found not only to inhibit CypA but also to reduce myocardial inflammation, which is a common fatality factor in COVID-19 . A study hypothesized that Ching-fang-pai-tu-san could provide a similar mechanism as CsA does  . I could not verify that yet.
Since there hasn’t been any research on phytopharmaceutical options for Cyp inhibition, I tried to figure out where the Cyp is synthesized. MetAP2 plays a key role in the synthesis of CypA  . However, inhibition of MetAP2 has adverse effects, especially on the endothelium and redox state . It’s hence no considerable target for a COVID-19-protecting agent.
Back to the CypA, there seems to be another inducer of CD147 which correlates well, namely Caveolin-1 (Cav-1)   . Cav-1 has been studied better for its potential in anti-cancer treatment. Triptolide, a component of Tripterygium wilfordii, has been found to inhibit the Cav-1/CD147 pathway and CD147 activity . Quercetin has shown to inhibit LPC-induced Cav-1 activation . α-Tocopherol was able to reduce Cav-1 expression below the one of the control group. Previously, I have surveyed the benefits of γ-Tocotrienol, another variant of Vitamine E, to inhibit the NLRP3 activation of SARS-CoV-2. Thus, a Vitamine E complex seems to be useful. Lastly, there is one contraindication, however. Curcumin seems to significantly increase Cav-1 expression .