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We Made One Gram Of Remdesivir

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Re: We Made One Gram Of Remdesivir

#91

Post by darawk »

djaque wrote: post #84
dguest wrote: post #73

Earlier quoted context omitted.

What branch of physics? There are hundreds of published null results looking for dark matter or Supersymmetry, for example. Instead of documenting a failed search, the papers focus on what versions of the theories the experiment excludes to 95% confidence.

I'm in acceleraror physics and study photocathodes. Unfortunately the state of those projects is that we thought a material should have great photoemission properties under some very specific circumstances. When we measured it, the material was actually terrible and we don't understand why it's that way outside of some speculation. Unfortunately it also feels like our lab doesn't have the type of expertise to explain…

> My advisor's explanation on publishing was that if we had great results that followed our initial theory of what's going on then we could write a paper and nobody would question it. But, now that we contradict theory the threshold of evidence is much higher and he doesn't want to go ahead with it.

Isn't that sort of the most important thing to publish? Something that contradicts theory means something new. Seems like all the more reason to pursue it, no?

Re: We Made One Gram Of Remdesivir

#92

Post by avian »

dguest wrote: post #85
avian wrote: post #72

Earlier quoted context omitted.

As someone who spent 4 years working on a PhD (wireless/RF technology) and then quit, your points 2 and 3 ring a lot of bells. I think "journal of failed experiments" is a wonderful idea.

Anyone can put a paper on arXiv. The bigger problem is that most journal editors will be skeptical of citing arXiv. If you're collaborating with more traditional academics it can be a challenge to even submit a paper with such citations. I've had to push my colleagues to cite a number of non-traditional sources: arXiv, github, and zenodo for example. Fortunately most of them agree that citations are cheap and that gi…

> Anyone can put a paper on arXiv.

Unfortunately as an academic it's really hard to justify spending time on writing up a paper that's only going to be published on arXiv. Regardless of citations, it doesn't count towards your publication quotas or PhD requirements.

Re: We Made One Gram Of Remdesivir

#93

Post by wuschel »

Vaslo wrote: post #34

In my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. There were three lousy things (for me) about the career that made me bail. 1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but rea…

Former chemist here. What are you doing in this life? Feel free to contact me - see email in profile.

Re: We Made One Gram Of Remdesivir

#94

Post by lisk1 »

rwmj wrote: post #88
rocqua wrote: post #68

Earlier quoted context omitted.

Doesn't that mean that Remdesivir would essentially defeat _all_ RNA viruses? Or is the effectiveness dependent on the exact RNA cloning mechanism used by the virus?

Yes, it was originally invented to treat ebola, but it's thought to have general antiviral properties against RNA viruses.

There are a lot more RNA virus specifically targeting antivirals surprised that most of them are not yet tested.

Re: We Made One Gram Of Remdesivir

#95

Post by DrAwdeOccarim »

ashildr wrote: post #74
kccqzy wrote: post #22

Remdesivir is an analog of adenosine, one of the four building blocks of RNA. Just look at the main structure and you'll agree they look similar. It turns out the mechanism of action of this drug is that it's supposed to be confused with adenosine, so that the viral RNA replication process uses remdesivir instead of adenosine, which later breaks the RNA†. Our body, or really, all biological processes can synthesize i…

This mode of action is fascinating, some HIV medications work in a similar way. What I’m curious about is why this huge group attached to the adenosine-like group is needed. It seems to be rather complex for being a shoe to be thrown into cellular gear. Do you have an idea or pointer into the mode of action of this group?

I'm not familiar with the synthesis development of remdesivir, but typically those side groups are discovered through a process called Structure Activity Relationship (SAR). The basic idea is you start with a bunch of different compounds (like 1000's) and look at their ability to interfere with a specific enzyme in a high-throughput screen. When you rank the 1000's of compounds, some will work better than others. Then you compare the structures of the top hits and look for similarities. So in this case those huge groups attached to the adenosine likley improve binding to the enzyme because they're greasy/hydrophibic.

So then you add different greasy groups to new compounds and screen those. So will be worse, but sometimes some will be better. Then you look at the better ones, like having a nitrile group off the 1' position of the ribose and maybe that started as an amine (I'm making shit up here) and they decided to make it stick further out (IDK).

Anyway, I did some quick looking at it seems like remdesivir is a prodrug that gets modified by other enzymes to become triphosphorylated and then incorporated into the RNA genome of the virus (https://www.nature.com/articles/nature17180/figures/1). So they got super lucky finding it! Check out that paper for the story.

Re: We Made One Gram Of Remdesivir

#96

Post by alkonaut »

roenxi wrote: post #19

Although very interesting, this article isn't a great introduction because a critical part of the picture is missing - the availability of the inputs. Sticking to simple stuff; mines produce iron at a rate measured in thousand-tonnes per hour with yields of potentially sub-30% compared to volume of earth moved. Ammonia and many acids are presumably measured in tonnes or kilograms produced per day. Low yields make the…

Exaxtly this. Are the inputs available and we can spend just a few tens of billions on building gigafactories to make this process parallel and controlled? Then it’s like making microchips from silicon or gold from ore. Terrible yield but cheap inputs and a scalable process.

If the inputs are expensive or the process can’t scale (to a billion doses in 12 months, say) then that’s worrying and perhaps indicates this isn’t a good candidate vaccine.

Re: We Made One Gram Of Remdesivir

#97

Post by orbifold »

girvo wrote: post #50
Vaslo wrote: post #34

In my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. There were three lousy things (for me) about the career that made me bail. 1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but rea…

> So many failures could be logged so I didn’t waste my time doing non-working or poor yielding reactions In a different but related world, clandestine chemists share failures more often than they do their successes, at least in the communities I was a part of a very long time ago. I'd wager this is because our substrates, reagents and solvents are such a pain in the arse to get compared to an actual lab, that wastin…

I actually think it is the same in chemistry, knowledge of which approaches don't work are a competitive advantage that is passed around under the hand. I've definitely observed this is in theoretical physics and pure mathematics, it is often much more important to know about things that have never been published then it is to read close to incomprehensible publications. So for example it is much more valuable to have attended the right seminars and have private copies of lecture notes, because by the time something is published it probably is out of date 1-3 years.

Re: We Made One Gram Of Remdesivir

#98

Post by malwarebytess »

lisk1 wrote: post #94
rwmj wrote: post #88

Earlier quoted context omitted.

Yes, it was originally invented to treat ebola, but it's thought to have general antiviral properties against RNA viruses.

There are a lot more RNA virus specifically targeting antivirals surprised that most of them are not yet tested.

sounds like we should get on it

Re: We Made One Gram Of Remdesivir

#99

Post by simlan »

rwmj wrote: post #86
Vaslo wrote: post #34

In my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. There were three lousy things (for me) about the career that made me bail. 1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but rea…

To what extent can synthesis steps be automated? Do you use a computer to plan how to get to a chemical? Do you use robots to carry out some or all steps?

In a usual lab no automation whatsoever. When something goes commercial there are two routes. One is adapting to bigger batches where you will get some automation (dosing, temperatur controll, mixing). The last step is to have full blown process where you pipe stuf from reaction a to b. However, that last one works best with large scale basic chemicals. Think all kinds of polymer materials.

There is a trend to get pharmaceuticals to a stage where flow chemistry can be used (like a small version of the full blown basic chemicals processes). This is however still a research field because a lot of processes don't lend themselves to continue flow.

The most automation in chemistry can be found in the analytical side of things. A good example right now are the covid tests that are run on large automated liquid handling systems.

Re: We Made One Gram Of Remdesivir

#100

Post by godzillabrennus »

Vaslo wrote: post #34

In my former life I was a graduate organic chemist, but I “quit” with a Masters. I loved Synthetic Chemistry as an undergrad and thought I wanted a PhD in. There were three lousy things (for me) about the career that made me bail. 1). So many syntheses have horrible yields just like this one. You’d start with grams of material to end up with micrograms. I loved solving these problems as an undergrad in books, but rea…

A great deal of published research is not reproducible regardless of field.
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