Cont: The One Covid-19 Science and Medicine Thread Part 5

There is a stage in drug discovery/drug development called "target engagement." Presumably one has previously been performing binding assays on a purified macromolecule, often a protein. In target engagement, one tries to determine if the same macromolecule is being inhibited, or is some other macromolecule being inhibited. The paper at the first link said in part, "These examples highlight the fact that demonstration of compound binding to a given target in a biophysical or biochemical assay using recombinantly expressed protein (or domain thereof) is in no way a guarantee of the same outcome being achieved when the drug is administered to a cell, much less a patient." The paper at the second link said in part, "An ideal assay would also measure: 1) the extent of target engagement, which can help to determine drug doses that produce efficacy at fractional target occupancy, while limiting side effects that might be caused by complete target occupancy; and 2) the potential for drug interactions with off-target proteins, such that efficacy and toxicity can be correlated with drug selectivity in vivo."

My questions regarding ivermectin and hydroxychloroquine with respect to Covid-19 are as follows: One, what is the proposed macromolecular target of each compound? Two, has someone attempted experiments regarding target engagement for either compound, and if so, what were the results?
 
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Well, they seem to be effective when treating scabies and malaria, respectively, but I don't know which macromolecules they target. :)
 
dann said:
There may not (yet?) be a way to distinguish between C19-related cases of many of these diseases and cases that are unrelated to C19.
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I just saw this:
Study uncovers distinct blood protein signature in children with Long COVID (News-Medical, Jan 28, 2025)
Pediatric long COVID marked by heightened inflammation, mirroring adult cases. Proteomic profiling achieved 93% accuracy in identifying affected children, paving the way for future diagnostic advancements.
(...)
The present study analyzed blood plasma proteins in children aged between 2 and 18 years from Rome, Italy, to identify unique inflammatory markers in Long COVID cases compared to healthy controls, MIS-C patients, and children with acute COVID-19.(...)
The study used Principal Component Analysis (PCA) to visualize protein expression patterns and highlight distinct profiles for Long COVID compared to other groups.
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dann said:
Well, they seem to be effective when treating scabies and malaria, respectively, but I don't know which macromolecules they target. :)
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Here is paper on the molecular targets of ivermectin. Here is some information regarding the targets of hydroxychloroquine. On the one hand, I would not care to make a blanket statement to the effect that one must always know the molecular target of drug before using it. On the other hand, I would say from both my reading and my personal experience that a contemporary program to find a new candidate drug will not go very far without this question being addressed and eventually answered in a satisfactory manner, as I hope that my previously linked articles made clear. Several years have elapsed since these two compounds were proposed as treatments for Covid-19. That should be enough time for such studies to have been started at the very least.
 
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A badly designed RCT might suggest that a drug has efficacy when it does not. But every drug has a target and a mechanism of action, even when that mechanism is unexpected. People who advocate for the use of either ivermectin or hydroxychloroquine for Covid-19 should be able to provide a hypothesis at the very least, but preferably should be able to produce data on how each compound works. For example, the active ingredient in Paxlovid targets the main protease of the virus. There is a structure showing the covalent bond between the two molecules.
 
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Chris_Halkides said:
Here is paper on the molecular targets of ivermectin. Here is some information regarding the targets of hydroxychloroquine. On the one hand, I would not care to make a blanket statement to the effect that one must always know the molecular target of drug before using it. On the other hand, I would say from both my reading and my personal experience that a contemporary program to find a new candidate drug will not go very far without this question being addressed and eventually answered in a satisfactory manner, as I hope that my previously linked articles made clear. Several years have elapsed since these two compounds were proposed as treatments for Covid-19. That should be enough time for such studies to have been started at the very least.
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Historically drugs were used because empirically they worked. Penicillin was observed to kill bacteria, trials showed it reduced deaths from infection, subsequently people discovered how it worked. Likewise (hydroxy)chloroquine. However nowadays screening does tend to be at the molecular level where drugs are screened for activity at a particular site or increasingly designed to be active at that site.

Most drugs aren't clean, they often have more than one site of action, although hydroxychloroquine was discovered as an anti-malarial drug its main use nowadays is as an anti-arthritis drug. Macrolide antibiotics like azithromycin or erythromycin are not only antibiotics but potent anti-reflux drugs, and have anti-inflammatory activity, particularly on the lungs, sometimes being used to treat asthma.
 
Meeting (1 of 2) of the Advisory Committee on Immunization Practices. Note, it's almost 8 hours long.

This is the new committee after RFK Jr. "retired" the prior group. There are 7 members.

The first segment provides intros by each of the members. backgrounds, Quals, etc.

The second segment is by the CDC going over C19 and Vax impact. It's very extensive. I watched this. A huge number of charts and tables providing great detail on the impact of C19. Filled in a few gaps in my knowledge.

The second segment by the CDC goes over Vax safety. I've only watched half of it. VAERs and V-Safe was Interesting. I was in the V-Safe program. Annoying to get texts every few days checking on your symptoms. Over time they reduced to every week then every month. For background, I had zero vax effects.
 
Interesting video on Long Covid. One of the best summaries of what's known/not known I've run across.
 
L.C. Barbarian on X, July 10, 2025
I had to see this with my own eyes.
@GoogleTrends search-term "memory issues" since 2004.
- We are in trouble.



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Nah, it's probably nothing to worry about. It was probably just the lockdowns ... or the vaccines ... or smartphones. It'll be over soon.
Or maybe not:
Adam Van Bavel on X, July 11, 2025
Looks like #Disability, but not quite as bad

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Denmark:
I don't know if the same pattern can be found in other Nordic countries, but in Denmark there has only been one really big summer wave, in 2022 when there was not one single day without C19 deaths: Covid-19 - Danmark
Look at the right-hand corner at the bottom of the page, "Nye indlæggelser pr. dag" (New hospitalizations per day) or go to "Dødsfald pr. dag" (C19 deaths per day).
The winter peak in 2022 coincided with the point when masking in indoor public places and all restrictions were abandoned. The next three peaks that year coincided with summer holidays and the return to work/school, October holidays, and Christmas holidays.
I think the summer waves in many other countries may be due to air conditioning and the tendency to stay indoors in insufficiently ventilated rooms during heat waves. The Nimbus variant appears to have come and gone in Denmark.
The level of SARS-CoV-2 in sewer water July 9 is "Very low".
 
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