structure-based drug design – The Laughing Wolf

COVID-19 16Apr20

Yes, I took a few days off. First, most of the news on COVID-19, aka Winnie the Flu/Xi Flu/Chinese Flu/etc., was political in nature rather than science based. Second, a lot of the more learned discussion had to do with models, and much of the really good discussions on that would be “inside baseball” to most people. Short version remains, however, that the prime model used for policy is seriously flawed and even with corrections is not yet close to reality. Until it is, it should not be used for policy decisions in my opinion. Third, I needed a break and got some other things done.

Before I get to the main topic for today, two quick notes. It is good to see that what was previously taboo is now going mainstream. Back two months ago, if you talked about the safety problems at both labs in Wuhan and even appeared to entertain the idea it could have been a lab accident, you were guilty of spreading false information and could be deplatformed. I’m glad several of us did, and even more glad to see some more open discussion of those problems and the possibility this started in a lab.

This article asks another taboo question that needs full and honest discussion. Given that the Chinese economy is brittle and was already in trouble; and, that Xi seized the opportunity to expand monitoring even as troublesome people were disappeared and various cleansings expanded, it is not outside the realm of possibility that Xi decided to level the world economic field a bit and make the most of it.

The main topic for today, however, is a study being breathlessly touted in the media for saying it is futile to develop a vaccine (and with some other slams). No, no it does not say that vaccine research is futile. Not unless you selectively edit the quote.

“Based on the close relationship of SARS-CoV-2 to SARS, current vaccine and drug development for SARS-CoV-2 has also focused on the S protein and its human binding receptor ACE2 (7, 24). Thus, the observation in this study raised the alarm that SARS290 CoV-2 mutation with varied epitope profile could arise at any time, which means current vaccine development against SARS-CoV-2 is at great risk of becoming futile. “

Let’s break this down and take on some of the media talking points.

Point 1: Until it is peer reviewed, and other studies confirm (or refute) it’s findings, I don’t trust it. Number of reasons, including that early studies can be like early reporting: full of errors and sensationalism.

Point 2: A finding of the study is that a mutation of COVID-19 has been found in India. That mutation, if you go to line 282 in the paper, actually makes that version less infectious as it reduces the ability to bind to ACE2 receptors. Did you get that? The mutation is less infectious, not more.

Point 3: Unlike some other covids and other viruses, the rate of mutation in COVID-19 is slow. If you go to line 229, this paper confirms that and even goes so far as to note “A relatively stable genome of SARS-CoV-2 is a good indication for the epidemic control, as less mutation raises the hope of the rapid development of validate vaccine and antiviral drugs.” Hardly the breathless gloom and doom implied by various headlines and discussion.

Point 4: Going back to the discussion above, changes in the S protein may make vaccine development targeted to that protein (and the related ACE2 binding) futile. Not all vaccines, just that target.

There are some other interesting points in the paper, but again it has to be taken with caution for now. As other studies replicate or provide information, a better assessment can be made.

As I discussed in a previous update that discussed structure-based drug design, viruses mutate. It’s a given. Some mutate slowly, some like an ADD squirrel in a field of nuts. Some mutations make the virus easier to catch, some make it more deadly, others can change receptors, symptoms, and more.

The fact is, however, that quite a few of those mutations are evolutionary dead-ends. Too deadly, and people die before they can transmit it. Less infectious (as seems to be the case discussed here), again, it is a strain that could die out well before others.

The key to vaccine development for fast mutations is to find targets that don’t change, because when those change that strain dies out. There are always such targets, the trick is finding them and finding ways to target them.

In conclusion, don’t let the MSM wind you up or be your main source of info. When it comes to false information, they lead the pack.

Since the media isn’t going to say it, once again, COVID-19 is not Capt. Tripps. It is not the flu or a cold. Chill, distance, and use good hygiene. STOP THE PANIC!

Also, a reminder once again: if you are sick or think you are sick, DO NOT GO TO WORK OR TO VISIT PEOPLE. Stay the frack home. Don’t be Stupid, go to work/out, and insist on getting up close and personal to everyone you meet. Yes, Stupid is capitalized as I work with Stupid, who did just that. Don’t be Stupid.

If my posts are enjoyable, helpful, or otherwise a benefit, please consider hitting the tip jar. Any help is very much appreciated, especially as I’ve been off work without pay since 27 Mar.

•My Amazon Wishlist

As always:

If you suspect you have COVID-19 or have been exposed: call your state health department and work with them so that you can be dealt with in a way that minimizes the chance of spreading the virus to those helping you and to the general public. Can’t get them? Call your local department or see if your health service has online/telemedicine screening set up; or see if one who has will let you use it even if you are not in their network. Do not go out in public, and don’t go to an ER or other facility without calling ahead. Be smart.

Use the interactive graphic to keep track of things. Is COVID19 an epidemic? Yes. Is it a Pandemic? Yes. Is there need for panic? NO. HELL NO. Should you be paying attention? Yes. Hell yes. Should you be preparing? Yes, better late than never. And good luck finding/getting stuff.

Want to avoid catching COVID19 here in the U.S.? Wash your flippin hands frequently, wash them thoroughly every time you use the bathroom, then follow with hand sanitizer after every washing, use hand sanitizer liberally when you can’t wash on a regular basis. Cover your mouth and nose when you sneeze, and stay away from those who don’t. Also, keep your bugger hooks out of/away from your eyes, nose, and mouth. Do NOT shake hands with anyone, and avoid touching or being touched by strangers. Or your strange friends.

Avoid travel if at all possible. If you have to travel, or go out for any reason, use lots of hand sanitizer and go to full flu protocols. If you have to use a public restroom, take full precautions including using paper towels and such to handle faucets, doors,etc. Believe it or not, this was highly recommended before now, and major grocery chains have long told employees to use those practices to avoid getting or spreading colds, flu, etc. Not many actually do it, but…

If you own a business, make sure your employees know the above protocols. Have someone who refuses to wash their hands or otherwise follow the protocols? Talk to them, write them up, and if necessary fire them as they now pose a risk of infection to you and your customers. Extreme? Yes, but while the CDC and others are working to slow it down, odds are it is already here and could hit hard and fast. Prepare for the worst and hope for the best.

I want to reiterate that there is no need for panic, but there is a strong need to be alert, be informed, and be prepared.

Good Sources Of Information On COVID-19

Instapundit (no longer doing roundups, but great articles from Glenn and his team)

South China Morning Post (decent, some salt may be needed)

Business Insider (decent, even if they did fall for some lies about Trump)

New England Journal of Medicine

Additional link to Johns Hopkins

More to come

Local Independent Businesses That Need Your Support

Oaken Barrel (Twitter at @OakenBarrel)

More to come

Other COVID19/COVID-19/2019-nCoV articles:

COVID-19 13Mar20 The Game Of Loads And Vectors Gets Real For America

COVID-19 12Mar20

COVID-19 11Mar20

COVID-19 10Mar20

COVID-19 9Mar20 The Game Of Loads And Vectors

COVID-19 8Mar20

Heh

COVID-19 7Mar20 How To Do It Right If You Have/Have Been Exposed To COVID-19

COVID-19 What Am I Doing?

COVID-19 2Mar20

COVID-19 1Mar20

COVID-19 29Feb20

Quick Additional Thoughts On The Bureaucracy

Panic Is Off And Running

COVID-19 28Feb20 Reasons To Hope, Reasons To Fear

COVID-19 A Plea To The Politicians (And Media)

COVID-19 27Feb20

COVID-19 Breaking A Chain?

COVID-19 26Feb20

COVID19 The Situation In China Gets Even Weirder

COVID19 25Feb20

COVID19 24Feb20 Raising DEFCON

COVID19 23Feb20

COVID19 22Feb20

COVID19 21Feb20: Just Look At The Blooms Dear

COVID19 Update 20Feb20

COVID19 Update

Update & Quick Thoughts On Preparedness

Expansion On A Theme

Well Maybe I Was Wrong

Some Quick Thoughts On Coronavirus 2019-nCoV

Why Should You Be Prepared?

Keeping Alert

Coronavirus And Practical Preparedness

COVID-19 29Mar20

This morning, I want to get a bit more into protein crystallography, vaccines, and why lockdown until vaccines are developed just won’t work. Meantime, my usual reminder that the mainstream media coverage is detrimental to the physical and mental health of you and those you love. Don’t give in to the deliberate and willful effort to incite panic and spread false information.

Vaccines have come a long way since cowpox and Jenner, or even the work of Pasteur. Part of that advancement is that we now have ways of studying the microbes down to a level where you can see the individual atoms that make up the subject of interest.

Proteins are the building blocks of life. In the case of some microbes (bacteria and viruses), they can be described as the building blocks of death. Understanding the structure of any protein helps scientists figure out what it does and how it does it.

One way to do so that I am most familiar with is protein crystallography. In simplest terms, you take a protein and grow a crystallized version of it. In most cases, there are several forms that can grow out of any single protein, so you have to isolate the particular structure that is needed. The crystals are usually grown in a drop of liquid that contains the protein, growth medium, and other factors related to the crystallization.

Once you have the crystal, you stabilize it and put it in the path of a “bright” (powerful) X-ray source and use sensors to record how the beam penetrates, doesn’t penetrate, or scatters. With a crystal of sufficient size, you can literally map out the physical structure down to the placement of the individual atoms. This data is then converted into a visual image of the protein in question.

Some of that imagery is quite spectacular. When I worked for NASA both times, I worked with the staff at the UAB Center for Macromolecular crystallography. At that center, they could and did grow crystals, on the ground and in space (which offers quite a few advantages, and analyze them. They had a system that could use that data to create a 3-D image that allowed you to examine the structure in detail, even rotate or isolate sections at need. With that information, treatments could be developed that would bind only with the desired target, allowing drugs to be developed that were more efficient and had fewer (or almost no) side effects.

What does this have to do with vaccines? For modern vaccines, everything.

To design a modern vaccine, you have to understand the structure of the organism against which you are vaccinating. First, all organisms mutate over time. Certain structures, however, have to remain the same or the organism is no longer viable and dies off. If you can identify those structures that can’t really change, you can design either a treatment that binds to that site; or, you can develop a vaccine that does the same thing to prevent it. For example, HIV had what was considered a high mutation rate which hampered development of vaccines. I know of at least one experiment that flew on the Shuttle to grow crystals to help identify the areas that could not change in order to develop a vaccine. Sadly, I don’t remember that effort being as successful as hoped. My memory is fuzzy, but I seem to recall that in the time available the crystals could not be grown to a useful size; but, again, my memory is fuzzy.

Again, understanding the structure is critical, as in many cases, you only want certain antigens or even a single antigen (a substance that produces an immune response by the body) to teach the body what it needs to fight against. When the vaccine is given, the antigen(s) in it cause the body to think it is being invaded and to develop an immune response that attacks the full/real pathogen when it enters the body.

Protein crystallography is one means of identifying the structure of a pathogen such as COVID-19. I know of one effort to use protein crystallography on COVID-19, and suspect there are more. So, between protein crystallography and other methods, targets for treatment and vaccine development can and have been identified.

For those wanting something more than this rather simplified explanation, may I suggest this paper, this paper, this paper, and this paper as starting points.

Now, we get to actual vaccine production. Despite the problems with the accuracy of information from China, we have genetic and structural information that identifies target antigens for vaccine development. These have to be isolated, grown in the laboratory, and then normally they would be tested on animals and then humans. The normal FDA approval process for drugs and vaccines has be circumvented, and the first of what will likely be several vaccines is now in human testing. Even with the shortened process, that still takes time, as in weeks to months to see how it works. If it does work and does not need refinement (this is where later vaccines will have an advantage), we can start giving it out, right?

Wrong.

Going from creating what could be as little as a few ounces needed for initial development and testing, you now have to manufacture hundreds, or even thousands, of gallons of a product that requires multiple stages to create while ensuring the highest possible quality. Even variations of the antigen being used have to be removed in many/most cases. Ramping up production will be a time consuming process. Again, we are talking months even with best case on development, production, and regulatory approval. In short, I think we are looking at somewhere between six to ten months in a best case scenario. I hope I’m wrong, but as noted before, you always plan for the worst, hope for the best, and take what comes.

Six to ten months in national lockdown is not going to work. The disaster that would be for the economy, not to mention to civil liberties, can’t be overstated. I can’t think of any rational person of any political persuasion who will stand for that.

Now, the above is greatly simplified. As above, if you want to know more about modern vaccine production methods, I recommend you start with this, with this, with this, this paper is a must read, this paper, and this paper. If you read those, I think you will better understand how miraculous both the current technology for studying things like COVID-19 is and the breathtaking pace shown in getting the first human trial underway. It literally could not have been done twenty years ago in my opinion, and quite possible even as little as ten years ago.

For those who want to know more about the work done at the UAB Center for Macromolecular Crystallography, I commend to you both what may still be available through NASA relating to Shuttle missions, and the papers and talks by Dr. Lawrence DeLucas, Charles Bugg, et al. For those who want to know more about the efforts to prevent paralysis from spinal cord injuries mentioned yesterday, you should look to the works of Borgens, Shi, et al at Purdue University.

Thus concludes today’s lecture. Yes, I have simplified things so that they are accurate though not necessarily precise. I wanted it on a level that could be widely understood. Hence the links to all the papers for those who want it in greater detail and precision.

Since the media isn’t going to say it, once again, COVID-19 is not Capt. Tripps. It is not the flu. Chill, distance, and use good hygiene. STOP THE PANIC!

If my posts are enjoyable, helpful, or otherwise a benefit, please consider hitting the tip jar. Any help is very much appreciated, especially as I’m now off for at least two weeks without pay.

•My Amazon Wishlist

As always:

I want to reiterate that there is no need for panic, but there is a strong need to be alert, be informed, and be prepared.

Good Sources Of Information On COVID-19

Instapundit (no longer doing roundups, but great articles from Glenn and his team)

South China Morning Post (decent, some salt may be needed)

Business Insider (decent, even if they did fall for some lies about Trump)

New England Journal of Medicine

Additional link to Johns Hopkins

More to come

Local Independent Businesses That Need Your Support

Oaken Barrel (Twitter at @OakenBarrel)

More to come

Other COVID19/COVID-19/2019-nCoV articles:

COVID-19 13Mar20 The Game Of Loads And Vectors Gets Real For America

COVID-19 12Mar20

COVID-19 11Mar20

COVID-19 10Mar20

COVID-19 9Mar20 The Game Of Loads And Vectors

COVID-19 8Mar20

Heh

COVID-19 7Mar20 How To Do It Right If You Have/Have Been Exposed To COVID-19

COVID-19 What Am I Doing?

COVID-19 2Mar20

COVID-19 1Mar20

COVID-19 29Feb20

Quick Additional Thoughts On The Bureaucracy

Panic Is Off And Running

COVID-19 28Feb20 Reasons To Hope, Reasons To Fear

COVID-19 A Plea To The Politicians (And Media)

COVID-19 27Feb20

COVID-19 Breaking A Chain?

COVID-19 26Feb20

COVID19 The Situation In China Gets Even Weirder

COVID19 25Feb20

COVID19 24Feb20 Raising DEFCON

COVID19 23Feb20

COVID19 22Feb20

COVID19 21Feb20: Just Look At The Blooms Dear

COVID19 Update 20Feb20

COVID19 Update

Update & Quick Thoughts On Preparedness

Expansion On A Theme

Well Maybe I Was Wrong

Some Quick Thoughts On Coronavirus 2019-nCoV

Why Should You Be Prepared?

Keeping Alert

Coronavirus And Practical Preparedness

COVID-19 28Mar20

If you need another reminder on why you should not go to the mainstream media for accurate and useful information, go read this. Right now, the media is the greatest threat to your health and safety, and those you love, out there.

Nor have the CDC, FDA, and NIH covered themselves with glory. The latest take down on how they got us in the position we are in is here. Some may chide me for attacking them, and I will admit that there are some good, very good, people working there. However, they are political agencies, not scientific or medical at this point. More on that in a moment.

Thanks to President Trump, who has to continually play whack-a-mole with the bureaucrats, a number of unnecessary regulations have been pulled out of the way. As such, there are new treatments coming on line, and testing is expanding in quantity and quality as the power of the American free enterprise system is harnessed to meet the challenges of COVID-19. Get the bureaucrats out of the way, and there is no challenge we can’t face.

In news not likely to be covered widely in the mainstream media, Dr. Didier Raoult and colleagues have published a second paper on the efficacy of hydroxychloroquine and azithromycin to treat COVID-19. Read the paper here, and when politicians say it won’t work and they make it illegal to prescribe, ask them why when three (more at this point I think) studies show it works.

Also, look at everyone standing up to help. You see it locally, and you can see it nationally when 9,000 retired Army medical personnel have volunteered to come back and help.

I was going to talk about vaccines and protein crystallization today, but the number of conspiracy theories about the pharmaceutical industry, while not deserving a reply, do give me a springboard to talk about the need to massively overhaul the FDA. This is something that has been bitterly resisted by the FDA, to the point of scorched earth, and by certain politicians with a vested interest. What vested interest? Go look up the Epi-Pen scandal and note but one politician who had a vested interest. They are not alone.

As a liaison to the Biotechnology Industry Organization (BIO) many years ago, I had the chance to meet one person named head of the FDA with a mandate from the then President to reform the agency, including updating the drug approval process. Sadly, they were not successful and what happened there is why I use the terms ‘bitterly opposed’ and ‘scorched earth.’

The first time I worked as a contractor for NASA, one of the scientific investigations that I came to learn a lot about involved protein crystallography for new drug development. Short version for today, if you can grow the right form of a given protein, it allows you to develop drugs that will bind with/act on it and not anything else. This greatly reduces the chance of side effects and makes for a more effective drug.

At that time, it took a minimum of five years and an average of $400 million to get through the FDA process. If, in the course of going through that process, you found a way to improve the drug, you had to start completely over again. By the end of my second time as a contractor for NASA, the cost had grown to $800 million.

Keep in mind, this is not the cost of research and development. This is just the cost to go through the FDA new drug approval process. I’m honestly scared to see how much the average cost is now, or how many years it takes. Means of improving the testing, and speeding the process up, have been known for years, but again were and are bitterly resisted by the FDA. These methods in no way impaired the safety of the public.

So, when you see drugs costing hundreds or thousands of dollars; or, you see drugs that can work on multiple diseases or conditions but are not FDA approved for them, this cost is why they are expensive and often not approved for other uses even when known to be safe and effective. Unless something has drastically changed (doubtful), you have to go through a process costing hundreds of millions of dollars, and lasting years, for each and every disease/condition.

Which is why even though Chloroquine/Hydroxychloroquine was proven effective against coronaviruses in 2005 (and ignored by the CDC), it was not approved for it. What company is going to spend hundreds of millions of dollars on approval when it has no realistic chance of a return on it’s investment.

Before I forget, on a similar topic, I worked with a researcher (couple actually) who developed a treatment that reversed paralysis from spinal injury, every time. He demonstrated it in animals repeatedly, and it worked if he could get to them within about 36 hours. The treatment prevented the formation of scar tissue in the spinal cord track that would block the regrowth of nerves, as they can and do regenerate if there is a pathway. When he tried to get approval from the FDA to do human trials, they said it had to be proven on patients who already were paralyzed from spinal injury – the people who already had scar tissue and on whom the treatment was unlikely to work. The FDA’s take was that no matter the animal studies, if it wouldn’t work on patients on whom it was almost impossible to work, then it was a no go. Last I heard, he was trying it there way even though there was almost no chance of success.

Thus ends today’s lecture. I really do want to talk more about protein crystallography, structure-based drug design, vaccines, and related topics. I find them fascinating, and they do have quite a bit of relevance to what is happening right now. That said, I intend to go have such fun as I can have in unpaid lockdown.

Oh, a quick frack you to Howard County here in Indiana. Books are always essential, and this strikes me as severe overreach that needs to be strongly and quickly addressed by the Citizens of said county.

Since the media isn’t going to say it, once again, COVID-19 is not Capt. Tripps. It is not the flu. Chill, distance, and use good hygiene. STOP THE PANIC!

If my posts are enjoyable, helpful, or otherwise a benefit, please consider hitting the tip jar. Any help is very much appreciated, especially as I’m now off for two weeks without pay.

•My Amazon Wishlist

As always: