Hydroxychloroquine and molecular covid-19 targets

The hydroxychloroquine issue has been quite politicized, with conflicting data as to whether it is efficacious for treating covid-19 or not. A new study was just released, identifying molecular targets for covid-19 protein interactions. It is quite an impressive study, considering the short time frame:

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

https://www.nature.com/articles/s41...d-id=61CF4C0767161E1D2B15C77665918141BC57D421

Note, it is behind a paywall, but the abstract is freely available. The most interesting part is the identification of two molecular targets for drug repurposing, inhibitors of mRNA translation and sigma 1 and 2 receptors. 29 currently FDA approved drugs are on the list of identified inhibitors for these targets, among them hydroxychloroquine.

Notably, the sigma 1 and 2 receptors are involved in Ca2+ homeostasis, which might explain the proposed use of Zn2+ as a cofactor. More interesting, PB28 was found to be 20-times more potent than hydroxychloroquine, the affinity of which is quite low.

Maybe there is promise for repurposing of other approved drugs? Time for more clinical trials.

 

It seems to me the CDC and MSM have gone to great lengths to disparage HCQ, and the likely reason for that is that MSM's biggest customer, Big Pharma, wants it that way. The profit margin on HCQ is miniscule because the patent ran out many years ago. They would prefer Remdesivir or vaccines, both with high profit margins.

 

That and orange man bad. Even though orange man bad didn't call it a "miracle cure" or a "game changer", he just said it could work. And for that, the national media betrayed the national interest. Though given the last four years, we expect nothing less from the national media.

 

I am glad to hear that Trump knew in early March that hydroxychloroquine would work, before any credible studies had been done. He must be some kind of magician, being able to predict the future.

Now, instead of the Trump adoration, anyone actually wants to discuss the paper at hand?

 

Is PB28 some sort of drug? Since it's more powerful than hydroxychoroquine with what it's supposed to do.

 

~ The drug is discussed at the end of this article :
https://www.baltimoresun.com/corona...uhbfmlkgzd6akt44mza-story.html?outputType=amp

 

Now, in a non-political world what should've happened is that they could've given the HCQ at first, but as they found new and better treatments to progress towards those. That's how medicine normally works, but orange man bad so if he names a prescription(or non-prescription) drug, it's time to panic.

 

Sure. I’ve been over it once and did a bit of looking into pb28. To clarify, the comparisons of micro molarity of pb28 and hydroxychloroquine in the study abstract only show it takes less molecules of pb28 than hydroxychloroquine to create the same effect in vitro. Since pb28 has never been used in humans (to my knowledge), let alone for treatment of viral infections, dosages are not known at all. So the increased potency of pb28 may be meaningless in vivo. Correct?

That said, the advantage at this point to the types of drugs including pb28 is there doesn’t seem to be any research showing negative side effects in short term animal testing.

I agree it’s time to fast track testing of these drug options. Cool thread.

 

~ Hydroxychloroquine is used in India as a preventative for healthcare workers - but the observational studies are inconclusive. They have determined it is safe for most who have no cardiac issues.

 

Affinity of the drug is VERY important in any drug development study. Most compounds wouldn't be considered usable if they have lower than nanoomolar affinity for the target. The reason is that the lower the affinity, the higher the needed dose. Higher dose increases the risk for off-target effects (manifesting as side effects). For example, hydroxychloroquine has off target effects on HERG potassium channels, which most likely is responsible for the cardiac side effects. PB28 does not seem to affect HERG.

 

PB28 is a sigma 2 receptor agonist.

https://www.sigmaaldrich.com/catalo...KQre5VR854oJJF_0TqvYuvQWyhwvvTg4aAujQEALw_wcB

The way you describe it is actually how it works. Drug developers don't care about politics, only whether the drug works or not. With that said, drugs can only be used if they are actually efficacious. That wad the problem with HCQ at the start, people didn't know if it was efficacious for treating covid-19, and the didn't know whether it had side effects for this use (i.e. would do more harm than good). Without double blind studies and more research, it was impossible to tell in early March whether HCQ was going to work.

If HCQ actually works, you won't find many people opposing its use. What people opposed was the peddling of the drug by Trump to downplay the seriousness of the virus and to support his reckless reopening agenda without a plan.

 

Unless you can actually prove any direct influence on reporting by the pharmacy industry, all you have there is an empty conspiracy theory.

The fact is that there are a whole range of COVID-19 treatments being proposed and studied, some involving generics and some involving proprietary medications (and some a combination involving both). Very little of that work was picked up by the mainstream media because it generally involves very dry, technical reports and no definitive conclusions yet.

Hydroxychloroquine only hit the mainstream after Trump ignorantly ran his mouth about it, leading to his supporters spinning up anything that could be perceived as positive and his opponents spinning up anything that could be perceived as negative. American partisan politics doesn't need any shadowy conspiracies to be a complete mess. I guess it's just harder to see that from the inside though.

 

I agree affinity is important. My point is simply we don’t know at this point if it will matter in this case. In vitro studies of hydroxychloroquine were called irrelevant so it seems disingenuous to try and put them against each other now based on in vitro affinity alone. And I know you are calling for in vivo trials. I’m not criticizing you, I’m criticizing the narrative one drug can be hyped with preliminary in vitro data but another can’t.

To clarify for third parties, by your “less than nanometer” cutoff point both hydroxychloroquine and PB28 have acceptable affinity? PB28 may have an advantage because it has no known side effects at any dosage not because of it’s affinity advantage alone?

Do you know of any side effects of PB28? The only good research I found was on tumor treatment in mice. There were no observable ones and tissue showed no toxicity.

 

I don't know anything about one drug vs another but calling reopening reckless while we still have large groups congregating to deface buildings, statues and set a fire or three seems disingenuous to say the least. We shut down businesses, outlaw Summer, close schools to prevent spread of this virus but large crowds dedicated to destruction are perfectly safe virus wise?

Get outa here!

Quit playing get the Orange man and open this country up and let's save what we can of our dignity.

 

Is Dr. Rault an incredible quack?

 

'Remdesivir good - HCQ bad - very bad.' FDA/GLD

"To better understand the mechanism by which these inhibitors exert their antiviral effects, we performed a time course assay in which the drugs were added at different times before or after infection (Fig. 6e). Cells were infected during a single cycle of infection at high multiplicity of infection (MOI = 2) over the course of 8 h, and the drugs were added either 2 h before infection or at 0, 2 or 4 h after infection. PB28, zotatifin and hydroxychloroquine all decreased the detection of the viral NP protein even in this single cycle assay, indicating that the antiviral effect occurs before viral egress from the cell (Fig. 6e). Furthermore, all three molecules inhibited NP expression when added up to 4 h after infection, after viral entry has occurred. Thus, these molecules seem to exert their antiviral effect during viral replication."

NATURE, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
David E. Gordon, Gwendolyn M. Jang, […]Nevan J. Krogan, Nature volume 583, pages 459–468(2020), Published: 30 April 2020.
https://www.nature.com/articles/s41...nd-id=61CF4C0767161E1D2B15C77665918141BC57D42

 

Don't know anything about him. What I do know is that his study had low numbers of participants and was not controlled.

 

So what? Especially in the middle of a deadly pandemic?
Over 1000 patients by 4/9.

Raoult has been proven right. OTOH, the movement to suppress the use of HCQ has been based on blatant science fraud.

 

I hate to wade into this **** because I know how leftists believe all doctors are geniuses and herd mentality takes over.

The virus doesn't kill you, your own body does. You don't have to kill the virus to survive, you have to prevent your body from having an autoimmune response that kills you. Obviously if some people have the virus and are asymptomatic then that tells you the virus itself isn't a killer, so to speak.

Deaths are a result of swelling and secretions in the lungs, which leads to oxygen deprivation and pneumonia.

Hydroxychloroquine can help with preventing swelling but it's not a targeted drug so in laymen's terms its effect gets diluted throughout the body. Anything that could prevent or help prevent swelling in the lungs is useful against covid 19.

Dexamethasone is a corticosteroid more on target with autoimmune responses....it helps prevent the swelling and thus helps survival rates. I know of someone who was in bad shape for weeks until he was put on Dexamethasone and then quickly improved.

Budesonide is like Dexamethasone...it's a corticosteroid. When taken with a nebulizer and ingested directly to the target area...your lungs... (thus bypassing dilution throughout the entire body) it effectively maintains your body's immune system to kill the virus while simultaneously preventing the swelling and resulting pneumonia when taken with an antibiotic such as a Zithromax (Z-Pack).

Big Pharma is chasing a vaccine for a virus that has mutated hundreds if not thousands of times already. Even if they come up with a vaccine, there is no guarantee it would prevent seasonal re-occurrences. Just like seasonal flu shots, they never work for all strains. This is how they make money.

If I get it, it's gonna be Budesonide and antibiotics within the first few days.

 

First the Left politicize it,
Then the Left laments that it's politicized?

Do they think they fool anyone?

​

 

They know that they fool damn near everybody, because they know the gullibility index amongst US citizens is very high.

 

I just made a note the Florida governor is begging for Remdesivar. Why do that when Trump has a gazillion does of Hydroxy?

 

You yourself noted there's like a gazillion doses(not really but the point is taken). There isn't as much remidisivr(and it's much more expensive). So when you run low, it really sucks.

 

First headline says that Trump, who is not a doctor, is wrong about HCQ studies. Trump went to an Ivy League school and he doesn't even seem like he graduated high school. So any statements by the orange idiot I don't believe at all. The second headline with the same author listed above said HCQ helped people survive better. What the means is if a patient is not at risk when he or she takes HCQ, meaning they will suffer cardiac issues. HCQ and zythorithmicin were given. Trump wanted people to take to prevent themselves from getting Covid. It's not that hard to see that Elizabeth Cohen did her job.

 

But if Hydroxy worked why bother?