https://www.technologynetworks.com/drug-discovery/news/drug-screen-identifies-niclosamide-and-ciclesonide-as-antiviral-candidates-against-sars-cov-2-334337 Korean researchers have screened 48 FDA-approved drugs against SARS-CoV-2, and found that 2, which are already FDA-approved for other illnesses, seem promising. The FDA approval for other uses would greatly reduce the time needed to gain FDA approval of use in COVID-19. The research is published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology. The investigators tested the drugs in Vero cells, a cell line developed from kidney cells of the African Green Monkey, which are commonly used to grow viruses for vaccine production. An anti-helminthic drug called niclosamide demonstrated “very potent” antiviral activity against SARS-CoV-2, according to coauthors Sangeun Jeon, Meehyun Ko, and their collaborators, of the Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam, Korea. “Not surprisingly, its broad-spectrum antiviral effect has been well documented in the literature, including antiviral properties against SARS- and MERS-CoV,” they write. A downside of niclosamide is low absorption, which undercuts the drug’s power by reducing the dose that reaches the target tissue. However, “Further development or drug formulation could enable effective delivery of this drug to the target tissue,” according to the report. Despite substantially lower antiviral potency, ciclesonide, an inhaled corticosteroid used to treat asthma and allergic rhinitis, also showed promise against SARS-CoV-2. Intriguingly, the investigators note that a study published earlier this year ( by Matsuyama et al.) a treatment report of 3 patients infected by SARS-CoV-2, demonstrated antiviral activity and revealed the drug’s molecular target to be a viral protein called Nsp15. “With its proven anti-inflammatory activity, ciclesonide may represent as a potent drug which can manifest [the] dual roles [of antiviral and anti-inflammatory] for the control of SARS-CoV-2 infection,” the investigators conclude. The anti-inflammatory activity might play a critical role in dampening or preventing the cytokine storms, an immune inflammatory overreaction that can kill COVID-19 patients. Reference: Jeon, et al. (2020) Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrobial Agents and Chemotherapy, DOI: 10.1128/AAC.00819-20
Note: The cold virus is a coronavirus.
https://pubmed.ncbi.nlm.nih.gov/29407486/Abstract
Human rhinovirus (HRV) infection causes more than 80% of all common colds and is associated with severe complications in patients with asthma and chronic obstructive pulmonary disease. To identify antiviral drug against HRV infection, we screened 800 FDA-approved drugs and found budesonide as one of the possible drug candidates. Budesonide is a corticosteroid, which is commonly used to prevent exacerbation of asthma and symptoms of common cold. Budesonide specifically protects host cells from cytotoxicity following HRV infection, which depend on the expression of glucocorticoid receptor. Intranasal administration of budesonide lowered the pulmonary HRV load and the levels of IL-1β cytokine leading to decreased lung inflammation. Budesonide regulates IL-1β production following HRV infection independent of inflammasome activation. Instead, budesonide induces mitochondrial reactive oxygen species followed by activation of autophagy. Further, the inhibition of autophagy following chloroquine or bafilomycin A1 treatment reduced the anti-viral effect of budesonide against HRV, suggesting that the antiviral activity of budesonide was mediated via autophagy. The results suggest that budesonide represents a promising antiviral and anti-inflammatory drug candidate for the treatment of human rhinovirus infection.
First of all the down regulation of MHC-1 by the orf8 protein isn’t an all or nothing event. As shown in the article you link to, there some MHC-1 still present on the cells albeit significantly less, likely this makes it harder for the body to initiate an immune response. Prior exposure to a vaccine, will most certainly help as it will prime T-cells to react rapidly upon recognizing MHC-1 loaded with viral derived peptides. The fact that infected cells may have fewer MHC-1 complexes, can of course make it less likely that the MHC-1 complex with viral peptides is recognized. None the less, you should be better of with primed T-cells due to vaccination, as long as you don’t stimulate an immune response towards self-peptides (eg an autoimmune response).
The spike protein is absolutely the best antigen on the virus, especially the highly conserved part responsible for binding to the human ACE2 receptor. If the we can stimulate production of antibodies inhibiting binding of the spike protein to ACE2, we can significantly impair the infectivity of mature viral particles. Additionally, the antibodies may help kill infected cells if they bind to antigens on the cell surface and trigger the complement cascade.
I would assume that most vaccines use some variant of the spike protein or induce production of some variant of the spike protein. Our antibodies can only recognize surface features of intact viral particles and infected cells, so the antigen need to be extracellular. Likewise, T-cell response due to recoqnition of MHC-1 with viral derived peptides require an intracellular peptide being loaded into MHC-1. The ideal vaccine against SARS-CoV-2 should initiate both T- and B-cell response for maximal protection.
Hope it helps,
Jeppe
I do not fear most of the chemicals you mention, why? Because dosage, pharmacokinetics and toxicity needs to be tested prior usage on the general population.
Like any other medicines, vaccines are put through animal studies and clinical trials.
Phase 1 to investigate safety profile of various dosages based on animal data.
Phase 2 to investigate efficacy and safety in a small group.
Phase 3 to investigate and prove efficacy and safety in a large group and investigate risks/benefits of treatment.
My only major concern is that we rush the deployment of vaccines without a full phase 3 studies. If we do so, we risk that the cure could be worse than the disease.
Ron Paul, a well know libertarian, is opposed to government edicts and is especially allergic when fudged numbers are used to justify those edicts. In Texas, the rising numbers of “cases” is being cited to justify governmental restrictions.
.
Shifting the definition of a “case”
Texas State Department of Health Services changing the definition of what constitutes a “Covid case” .... [causing] the mainstream media [to declare] that a “second wave” was on the way ... and that cases were "spiking." ...on May 18th, it was revealed that while previously the determination of a Covid “case” was a confirmed test result, the definition was suddenly changed to count “probable” cases as “cases.” At the same time, the threshold for determining “probable” was lowered to a ridiculous level. As Judge Hill said at that May 18th meeting, “If you have a subjective fever ["I feel hot"] and you have a headache and you live in Collin County, you now meet the qualifications to be a probable COVID patient. And “probable cases” were considered cases. Even worse, once a “probable” case was determined based on possibly unrelated subjective criteria, up to 15 people in possible contact with that “probable” case were also listed as “probable cases.” And “probable cases” were considered cases. ...Is it any wonder there was a “spike” in “cases”?This confirms my impression that it is best to count hospitalizations and deaths as the number-of-cases metric is just too easy to fudge.
A Belgian doctor sent an email advocating the use of Thymosin Alpha 1 in the treatment of SC2, and indicating it ‘decreases mortality by 66% in severely affected COVID patients’.
Here is a small retrospective study from Wuhan of the use of Thymosin Alpha 1 in Sars-Cov2 treatment:
Thymosin Alpha 1 (Tα1) Reduces the Mortality of Severe COVID-19 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells
https://pubmed.ncbi.nlm.nih.gov/32442287/
I also came across this short article, which indicates the peptide was also used as a prophylactic with classic SARS in China:
https://covid19immune.com/articles/peptides/thymosin-alpha-1
Some highlights:
Thymosin α 1 (Tα1) is a naturally occurring 28-amino-acid peptide originally isolated from thymus. It acts both as an immune modulator and direct-acting effect.1 Tα1 has been widely used and tested in a broad range of clinical applications including viral, fungal and bacterial infectious diseases, cancer and as a vaccine enhancer. Due to its biological properties and safety profile Tα1 could be used as a protective agent in the elderly subjects with a higher susceptibility to infectious diseases. Many people in China used Tα1 as a prophylactic agent against SARS-COV during the 2003 pandemic.2
Thanks for clarifying. I was able to understand the details of your response, much appreciated. It is encouraging. Have you looked at the German study that speculated prior exposure to other coronaviruses might have boosted T-cell response to SARS Cov-2? Do you think it means anything for those who get regular flu shots?
New Zealand report “probable” cases, also. It’s definition of a probable case is:
A probable case is one without a positive laboratory result, but which is treated like a confirmed case based on its exposure history and clinical symptoms.This can catch false negatives (which could be 20%-30% of tests, according to our Director General of Health) and cases where a test just can't be done (e.g. with small children or dementia patients). We haven't had a probable case for so long that it's stopped being mentioned in updates, though they still appear on our official tally.
Those are interesting studies!
The UK found that oral or IV dexamethone helped their NHS patients who were under respiratory distress.
https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf
Chris’s videos have reviewed the MATH protocol, which also employs a steroid in hospitalized patients.
The Japanese study referred inhaled ciclesonide in three patients with pneumonia.
With regard to the Texas doctor using budesonide, wasn’t entirely clear to me what the status of his patients were (but I didn’t watch the whole video).
This “rapid review” looked at the data on both ciclesonide and budesonide, but the in vitro data from a single study didn’t support an antiviral or anti inflammatory mechanism for budesonide.
https://www.cebm.net/covid-19/inhaled-corticosteroids-a-rapid-review-of-the-evidence-for-treatment-or-prevention-of-covid-19/
So it looks like inhaled steroids might help people in respiratory distress, but we need more data on budesonide, it seems. Maybe the doctor could write up a case series with the pertinent details on his patients. He is obviously excited about what he is seeing.
Wonder if there is any information on COVID in people with asthma who use inhalers or nebulizers. I would think they are at high risk due to a preexisting condition, but on the other hand, what if COVID symptoms prompt use of their inhalers earluy on - does that make any difference?
To clrify: This “rapid review” looked at the data on both ciclesonide and budesonide, but the in vitro data on budesonide didn’t support an antiviral or anti inflammatory mechanism
https://www.cebm.net/covid-19/inhaled-corticosteroids-a-rapid-review-of-the-evidence-for-treatment-or-prevention-of-covid-19/
Thank you for the reference… but I am confused about your comment relative to it;
This "rapid review" looked at the data on both ciclesonide and budesonide, but the in vitro data didn't support an antiviral or anti inflammatory mechanismBut here's what the paper says, and it seems like the opposite of what you are saying above, at the case of the Japan steroid;
The authors compared the drug effectiveness of ciclesonide, an inhaled corticosteroid medication used to treat asthma and allergic rhinitis, against the drug effectiveness of chloroquine, lopinavir and remdesivir as reference drugs. They found that ciclesonide had an IC50 of 4.33 μM, which was much lower than that of chloroquine (9.12 μM), lopinavir (7.28 μM) and remdesivir (11.41 μM). The authors therefore proposed that ciclesonide exhibits a direct acting anti-viral activity in addition to its intrinsic anti-inflammatory function.So ciclesonide sounds like the bomb, no? Edit: I see you corrected yourself... Thank you again for the paper.
Where “probable” has a suddenly new and more flexible definition.
Wow. That’s a scam. To say the least.
If we look at this from another viewpoint, however, it is the mark of desperation. If deaths continue to decline, while cases scream higher, the pandemic will start to seem like a real nothing-burger due to the rapidly declining CFR.
“Everything that happens in an election year - is about the election.”
It looks like it disappears pretty quickly if you have a mild case. Also it looks like Spain has not come anywhere near 60% exposure.
https://www.businessinsider.com/coronavirus-antibodies-study-herd-immunity-unachievable-spain-2020-7
Yes, but why did the people who tested negative or later tested negative have a mild case?
- Was their immune response primarily or entirely not an antibody response (i.e. the T-cell response that has been documented)? If so, why wouldn't they just respond the same way with a mild response next time? Why wouldn't it be even milder because of some undetectable or not tested residual immunity?
- Was it due to a low innoculum? In this case, one might expect a more severe case next time. On the other hand maybe there is some residual immunity that would make this less likely. Or some hidden damage from round one could make it more likely.
- How many people never tested positive, had a mild or very mild case and now have no detectable antibodies? Why couldn't their next exposure result in exactly the same outcome?
In thinking about the question of why the origin of the SC2 virus matters, I would add that it matters because > 500,000 people have died (so far), > 11 million have been infected by the virus (so far), and countless others have had their livelihoods impacted. Someone, or some individuals need to be held accountable. If the pandemic was naturally occurring, then we could accept it, but if it was man-made, then it is not acceptable. Blame must be laid!
Australia has pushed for an independent investigation into the origin of the virus, and the handling of the pandemic. This is very important and hopefully it goes forward.
https://www.sbs.com.au/news/coalition-of-116-countries-back-australia-s-push-for-independent-coronavirus-inquiry
Even if you got to 50% , you would quickly start loosing immunity as well. Until everyone gets this 2 times per year , which is what I think the vaccine will require about 3-4 years of 2x /yr before this is really put away. That is a lot of taxing the immune system. I do not believe in vaxxing. But for older people , and sick people , there may be no choice , even young people , there may be no choice. problem is older people do not build antobodies and react as strongly to vaccines ( flu ) as younger healthy people… So will it even work with them? or can be more like the flu, it will not work as well in the people who need it. But this may be the best argument to vax younger people… as to protect the older people… who are technically minimally vaxable.
To add to the point made by JWhite on how this has affected all of us.
First, we pay for this research. For example, the research published in 2015 paper on chimeric Frankenviruses was funded by NIH (specifically NIAID, headed by Dr. Anthony Fauci), National Natural Science Foundation of China, and the NGO, EcoHealth Alliance, which gets funding from USAID and NIH. We, the public, funded this, they are accountable to us.
Second, as this community knows, this GOF research is very dangerous because of the pandemic risks that accidental release would pose. Because of objections raised within the scientific community, the research was “paused” in 2014 and “resumed” in 2017. Here’s what the article cited above states:
Experiments with the full-length and chimeric SHC014 recombinant viruses were initiated and performed before the GOF research funding pause and have since been reviewed and approved for continued study by the NIH.So whoever decided this was a good idea despite the risk should be held accountable . Third, because people affiliated with this research (such as Dr. Peter Daszak, President of Ecohealth Alliance) have been saying to the media that there is no way this could have come form a lab, even though they have been finding this very research into genetically engineered viruses that posed a risk of escape. This characterization is misleading, to say the least. Those decisionmakers who are directly involved but silent, those who conducted the research but are silent, and those surrogates who are involved but saying "nothing here to see", should be called out. This CNN headline from 2017 is pretty direct: https://www.cnn.com/2017/12/19/health/nih-deadly-viruses-bn/index.html
So here’s a timeline:
In this paper from 2013, Dr. Peter Daszak, Dr. Shi and colleagues isolate and characterize a SARS-like coronavirus from Chinese horseshoe bats from a cave in Yunnan province (some distance from Wuhan). They discover that, like the epidemic strain SARS-Cov-1 (but unlike other SARS-like coronaviruses), the spike protein of this isolate binds human ACE-2. They name this bat SL-CoV-WIV1 (initials seem obvious).
https://www.nature.com/articles/nature12711
we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples ...which has typical coronavirus morphology ... and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry...Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs.I would note that bats were not sold in the Wuhan market and that the above bat SARS-like virus (WIV1) uses human ACE-2 receptor and needs no intermediate host. Next is the 2015 paper cited in previous posts, in which Dr. Shi and colleagues create a chimeric SARS Cov virus with a distinct S protein and a SARS Cov genetic backbone, and show that it infects and replicates in human lung cells, causes pathology, and is recalcitrant to neutralization by antibodies because of its novel spike protein. https://www.nature.com/articles/nm.3985 In 2017, after 5 years of surveillance studies in bat caves, they identify 11 more SARS-like strains from bats in Yunnan province, which differ significantly in the S gene and the ORF8 reading frame, among other sequences. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006698 (I mention these in particular because in SARS Cov-2, the S protein is the key that unlocks the ACE-2 receptor and the ORF8 down regulates MHC expression on human T cells, which would reduce the degree to which these immune cells recognize the virus as foreign). Much of the paper is devoted to genetic characterization, but one section is noteworthy from our standpoint:
Using the reverse genetics technique we previously developed for WIV1 [presumably the 2013 isolate], we constructed a group of infectious bacterial artificial chromosome (BAC) clones with the backbone of WIV1 and variants of S genes from 8 different bat SARSr-CoVsSo they constructed artificial chromosomes containing the genetic backbone of the bat SARS-Cov WIV1 (that they believe was the progenitor to SARS-Cov-1) but with various different spike protein genes spliced in. So 8 chimeras. (It has been asserted in the press that this technique does not leave a signature of artificial manipulation). Two of the eight chimeras were cytotoxic to monkey cells, so evidently they obtained replicable virus via the technique of infecting with artificially reconstructed bacterial chromosomes containing the requisite viral genes.
When Vero E6 [monkey] cells were respectively infected with the two successfully rescued chimeric SARSr-CoVs, WIV1-Rs4231S and WIV1-Rs7327S, and the newly isolated Rs4874, efficient virus replication was detected in all infections.The two engineered viruses, and an additional wild-type virus, were able to use ACE-2 receptor to infect human cells.
To assess whether the three novel SARSr-CoVs can use human ACE2 as a cellular entry receptor, we conducted virus infectivity studies using HeLa cells with or without the expression of human ACE2. All viruses replicated efficiently in the human ACE2-expressing cells.Conclusion: I think we can conclude that many SARS-Cov viruses have been engineered in a lab, and some of the details have been published. This group first discovered a SARS-Cov virus from bats that infects human cells directly via ACE-2, then artificially engineered this SARS Cov-1 type virus by manipulating the spike protein in multiple ways over time. Various artificial chimeras were produced that infect human cells via ACE-2, replicate efficiently in human cells, cause pathology, and in some cases resist neutralization by antibodies. We know that in SARS Cov-2 has a SARS Cov backbone and a spike protein distinct from the SARS Cov-1; and that the S gene includes a 12-base-pair insertion for a cleavage site that makes the spike protein effective at using ACE-2 for cell entry. SARS Cov -2 also has differences in other sequences, such as ORF8, which these researchers found to be diverse in different bat corona viruses. Could SARS Cov-2 have come from a lab? Of course the possibility exists. Engineered SARS-Cov viruses made in Wuhan are a reality, not a hypothetical. Just as an aside, interesting to see how far Yunnan province, site of the bat caves, is from Hubei Province where Wuhan is situated.
pCoV-MP789 from Malaysian Pangolins found close to the Yunnan border + RaTG13/4991 from Rhinolophus Affinis bats found in Yunnan province + cleavage site insertion and we are done.
Accessions pCoV (MT121216), RaTG13 (MN996532) and it’s original RdRP of 4991 (KP876546)
No need for a SARS-CoV backbone or anything else. These three items match nCoV-2019 by 99.6%. Even SL-CoV ZC45 (MG772933) has a better binding affinity than SARS-CoV, so there is absolutely no need to use the SARS-CoV backbone when much better candidates exist.
While I can prove this was made in a lab, I cannot prove which lab or country this came from.
Also and for clarity, RaTG13 came from 870 miles west of Wuhan. WIV01 (KC881007) was not the basis for SHC014 (KC881005) nor was it the basis for hACE binding. That was SL-CoV-Rs3367 (KC881006) as referenced in the original 2013 publication.
Rs3367 (Rs being Rhinopolus sinicus, commonly found in Yunnan) was sampled on 19, March, 2012 whereas WIV01 was sampled 18, September, 2012. They were both used in the publication but 3367 was the basis of their research in 2012. After their findings, they pushed SHC014 for chimeric adaptation. Nonetheless, all 3 viruses come from the Chinese Rufous Horseshoe Bat (Rs).
The bigger story is that RaTG13 was discovered as SL-CoV-Ra4991 3 months before the 2013 publication was submitted. No chimera required there!!