[kccqzy]

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 incredibly complicated molecules that can take human chemists a huge amount of effort to synthesize. It really is amazing how awesome our body is.

†: My description here is a dumbed down description. For a more precise description see section 2 of Arguments in favour of remdesivir for treating SARS-CoV-2 infections, Wen-Chien Ko et al, https://www.sciencedirect.com/science/article/pii/S092485792...

[koboll]

This is such a great description. Compare how Wikipedia describes the same process [https://en.wikipedia.org/wiki/Adenosine#Research]:

> The adenosine analog NITD008 has been reported to directly inhibit the recombinant RNA-dependent RNA polymerase of the dengue virus by terminating its RNA chain synthesis. This interaction suppresses peak viremia and rise in cytokines and prevents lethality in infected animals, raising the possibility of a new treatment for this flavivirus.

Absolute gibberish to someone with limited knowledge of biology.

[aaai]

May be hard to understand for ppl. with no background, but that description includes the crucial bit of information that OPs "easy to grok" simplified description lacks:

> inhibit the [...] RNA polymerase of the [..] virus

If it would just simply stop RNA synthesis (eg. inhibit any RNA-polymerase) or if it would actually break RNA in general, it would kill HUMANS just as well!

The point of antiviral compounds is to selectively inhibit/kill mechanisms/components of the virus and not the human host... there's hundreds of thousands of antiviral and antibiotic compounds that are not very useful because they'd kill humans just as well or give them horrible cancers or god knows what else...

As the saying goes... "Everything should be made as simple as possible, but not simpler."

[kohtatsu]

I noticed that hand waving in the OP too.

Any insight on how it manages not to harm non-virus stuff?

(Not a biologist. Also you're using a lot of italics and it harms the readability at least for me.)

[oefrha]

Scientific articles on Wikipedia aren’t written for laymen, although some could be understood by laymen as a side effect. For example as a physicist/mathematician I expect precise and physically/mathematically accurate statements rather than hand-wavy analogues that the average Joe might be able to make sense of, and that’s how I edit. Now, it’s okay to also include more approachable explanations, but they’re not a must.

[munificent]

From: https://en.wikipedia.org/wiki/Wikipedia:Writing_better_artic...:

> Wikipedia is an international encyclopedia. People who read Wikipedia have different backgrounds, education and opinions. Make your article accessible and understandable for as many readers as possible. Assume readers are reading the article to learn. It is possible that the reader knows nothing about the subject, so the article needs to explain the subject fully.

[nitrogen]

I know Wikipedia has evolved considerably from its original intent, but isn't one of the quintessential goals of an encyclopedia to have an approachable summary of every topic?

[leetcrew]

Wikipedia isn't quite like a traditional encyclopedia in this regard. it covers many technical topics that would be too niche to include in the latter.

random example: take a look at the Wikipedia article for "currying". [0] while quite accessible to someone with a math/cs background, this would be pretty much unintelligible to someone who wasn't familiar with the notion of a mathematical function. perhaps it could be rewritten to be even more accessible, but what would be the point of explaining currying to someone who doesn't know about functions and arguments in the first place? brittannica doesn't even cover this topic.

[0] https://en.wikipedia.org/wiki/Currying

[nitrogen]

The concept of partial specialization can be useful in many ways. I could see the concept of applying a process to one process and getting a new process for creating processes as somewhat applicable to business analysis, process engineering, analysis and design of government, etc.

I know Wikipedia isn't supposed to be a textbook, but I'd argue that having a more accessible first paragraph or summary section on every topic could help all uses:

- Specialists would more easily be able to refresh their memories of topics they use infrequently before diving into the details.

- People in neighboring specialties can more easily branch out.

- Informed laypeople (e.g. experts in other industries) could more easily find new ideas for cross-pollination into their own field.

As one random example I have recently found application for an algorithm mainly reserved for use in geophysics and cartography to audio signal processing, but learning and applying it took way more research than it really should have.

[acqq]

> I know Wikipedia isn't supposed to be a textbook, but I'd argue that having a more accessible first paragraph or summary section on every topic could help all uses

I'm curious how you would rewrite that first paragraph then:

"In mathematics and computer science, currying is the technique of translating the evaluation of a function that takes multiple arguments into evaluating a sequence of functions, each with a single argument. For example, a function that takes two arguments, one from X and one from Y, and produces outputs in Z, by currying is translated into a function that takes a single argument from X and produces as outputs functions from Y to Z. Currying is related to, but not the same as, partial application."

BTW I don't like that paragraph, it looks to me that it completely "misses the point" because as far as I understand currying is not about the sets but about the arguments. If it would be about the sets it would be just "a rewrite to a function that accepts the subset of the previous input set" and it's not about that.

[aaai]

"Approachable" means that it might require some effort from the reader (eg. in worst case scenario, a reader not familiar at all with the domain would have to look up the definition of every word in a sentence and do that recursively a few steps, until he/she gets some domain familiarity by reading the equivalent of a few hundreds pages or less), but you can approach it, and in exchange it gives precise and rich information!

I like Wikipedia as it is, let's not make it into IdiocracyPedia for the sake of accessibility... if you're not lazy and you're willing to put some focus and time into your research you'll be able to understand quite unfamiliar subjects from Wikipedia, there's nothing blocking you, as opposed to eg. lots of academic articles that may contain un-google-able jargon and unexplained/unmentioned domain specific assumptions.

[Isinlor]

I've done undergrad level mathematics and a lot of Wikipedia articles about mathematics is complete gibberish to me even if I put a lot of effort (hours) in understanding them. My estimate would be that more than 99% of population would not be able to gain anything from reading them.

[SkyBelow]

Wouldn't this be what the simple version is for? One is to be informative to people who know nothing, the other is to be informative to the people who want to learn about it at depth.

[C4stor]

This a the fallacy of choice in action. People who want to learn about a subject at depth are still helped by simple and accessible descriptions. Simple doesn't have to mean wrong, but can rather mean "a human invested a lot of thoughts producing those words so that all others don't have to". This is in my opinion the great way of doing simple, and it definitely has its place on wikipedia.

If you're not convinced, even professional scientists themselves regularly publish and read "review papers" which are pretty much papers doing no research other than summariing and simplifying the current state of the research in their field.

[SkyBelow]

>People who want to learn about a subject at depth are still helped by simple and accessible descriptions.

I don't see this as being always true. For example, scientific papers are written in such a way that normally you need a great deal of understanding in a field to read them. Making them accessible would mean either removing or explaining all domain specific knowledge in each paper. Expecting the reader to acquire the knowledge elsewhere and then read the paper with the knowledge makes a group of papers more accessible than if each paper did either of the options making them simple.

In the same way, the wikipedia page on integration by parts does a better job of explaining what it means than if it took the time to explain what a function is, what a variable is, what an integral is, what a product is, what an antiderivative is, or what the common notation it uses. I bring these up because these are all assumptions made before you even get to the table of contents of the article. If the article was simple enough that someone who didn't know any of those concepts could understand the same information presented in the first paragraph, you would have a significant introduction to mathematics that would slow down those who have some basic calculus knowledge seeking to refresh or get a summary of what integration by parts is.

[pnathan]

I have almost no knowledge of biology past a weak high school education and that sentence gives me an approximate understanding. It's not gibberish if you look at what it says and carefully read it.

[m-p-3]

One article among many others that would benefit from being simplified on simple.wikipedia.org

[C4stor]

And yet, 21 hours after making this remark, noone cared enough to edit the article to include the "great description".

Wikipedia isn't magical. If you don't care enough to edit it, it won't include the information you'd like to see.

[a123b456c]

Author called it a dumbed-down description. Are you sure that belongs on wikipedia?

[C4stor]

Sure, why not ? Let's consider for example https://en.wikipedia.org/wiki/Linezolid , it's quite clear what it's used for but if you dive in the "Interactions" paragraph for example, it's definetely not a dumbed down article overall.

[whatshisface]

Gibberish to someone with limited knowledge of biology, but significantly more informative for someone who is using Wikipedia as a reference source and not a textbook.

[javajosh]

I'm not so sure about that. I've read wikipedia articles about subjects I know well and found the language to be needlessly packed with jargon such that it could at least momentarily dazzle and confuse the inventor of the subject himself!

Rigorously precise language (e.g. "jargon") is almost never needed for a top-line description of a thing, and I think should be discouraged, in general. Yes, highly technical descriptions targeted toward professionals and academics in the field have their place in wikipedia, but ought to be relegated to periodic additions to the body of the article. That's just my opinion, of course, but as such I think its quite correct and admirably justified!

[prewett]

Feynman shared your opinion, so I’d say you’re in good company!

[vikramkr]

I agree in general, but in this case the extra information is sort of irrelevant - do we really need to say "in this flavivirus?" Something much better as an overall description might be "Remdesivir is an adenosine analogue that chain terminates RNA dependent rna synthesis, inhibiting viral replication" or something like that. Use the molecule name instead of a label, general instead of specific, and if you are talking about dengue in particular - why refer to it as a flavivirus? Who cares in this context? Just say "dengue" again instead of "this flavivirus." And, I don't think the drug has been empirically demonstrated to inhibit cytokine storms etc, that should qualify the description of the imputed mechanism of action by clarifying that it's the hypothesized effect the drug will have.

[pfdietz]

There has been exciting work on directed evolution of enzymes for drug synthesis, particularly for transamination (conversion of a ketone to an amine). This is I believe being used commercially now, for example for the production of the diabetes drug sitagliptin.

https://blogs.sciencemag.org/pipeline/archives/2010/10/06/ch...

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002...

[ashildr]

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?

[DrAwdeOccarim]

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.

[ashildr]

Thanks, I’ll have some reading to do on easter, now :-)

[HarryHirsch]

The observation is correct. Remsedivir is a prodrug, the active compound looks like adenosine monophosphate. But that molecule bears too much charge to be able to cross cell membranes. Consequently medicinal chemists put protecting groups on the offending atom, to help the compound get out of the bloodstream and into cells. Once inside, those are cleaved off through nonspecific esterases and the molecule can't get back out.

It's all part of ADMET (absorption, distribution, metabolism, excretion and toxicity) optimization. Pharmacokinetics is an important subject, and that's why you can use the "XY shoved activity in vitro" papers only as starting points.

[ashildr]

Thanks for the good explanation of how Remdesivir enters a cell and stays there.

[ImaCake]

So looking at the wiki page image of Remdesivir [1] I can see that this looks a lot like the sugar-phosphate backbone that is integral to DNA and RNA. If you imagine DNA as a curling ladder, the nucleoside (adenosine) is the steps, and the sugar-phosphate pairs make up the rails on either side of the steps.

The adenosine bit is attached to a five carbon sugar (pentagon with O at top) which is identical to the sugar it would be attached to in RNA. The next thing along is a phosphate with some oxygens double bonded to it, which is part of the "backbone" of DNA. The stuff attached to that phosphate is nothing like DNA or RNA.

Hope this makes sense and provides a little insight for you :)

1. https://en.wikipedia.org/wiki/Remdesivir

[ashildr]

It does, thank you!

[xg15]

Out of curiosity: We seem to have a very good understanding how synthesis in biological processes works (from DNA to the eventual molecules), we are able to create DNA/RNA molecules with arbitrary content and we're increasingly able to simulate what molecule a particular nucleotide sequence would produce.

So, putting the three together, would it be possible to use actual biosynthesis for designed molecules by basically writing your own DNA/RNA and inserting it into a cell?

(Or is this already what's being done?)

[cowboysauce]

in theory it's possible, in practice it's not. DNA encodes the information on how to produce to proteins. Proteins can catalyze chemical reactions. But there's no straightforward to look at a nucleotide sequence and figure out what it's corresponding protein does. Nor can we design proteins with arbitrary functions.

The entire thing is so unimaginably complex. For example, for a lot proteins that are catalysts (aka enzymes) the actual catalytic part is a metal ion and the protein mostly provides scaffolding. A nucleotide sequence alone doesn't directly tell you what ion is needed. In some cases, multiple ions can fit, but only one actually results in the protein work. This the basis for how a lot of toxic metal exert their toxic effects.

It's also not as simple as a nucleotide sequence codes for a protein and that's it. Proteins fold into their final shape from the chain of amino acids that DNA encodes. Protein folding in general is a hard problem. Biological proteins may have other proteins (called chperonins) that help them fold into their proper configuration. Then proteins may also be modified after they've folded (again by other proteins). Some proteins are made up of multiple sub-units as well.

[xg15]

Thanks a lot for the info.

> Proteins fold into their final shape from the chain of amino acids that DNA encodes. Protein folding in general is a hard problem.

My hope was that we had made progress in exactly that domain. Yes, the relationship between a nucleotide sequence and the resulting protein is extremely complex, but my impression was that we have tools to simulate the folding process for a given chain of amino acids (Folding@Home comes to mind).

So I was imagining a brute-force like process, where you (somehow) start with some candidate sequences, simulate how they would fold and use the sequence that comes closest to the molecule you wanted to have in the first place. Of course this only works if your target molecule can be assembled out of amino acids.

[bewaretheirs]

Transgenic goats have been produced which secrete drugs in their milk -- one transgenic female goat can produce about six pounds a year of human antithrombin, a blood thinner, in her milk.

From 2009: https://www.nytimes.com/2009/02/07/business/07goatdrug.html

[l33tman]

Yes, this is already being done (since long) by many different research groups and industrial companies with various levels of ambition (it's normally not needed nor feasible to design everything completely from scratch though).

If you want an easily accessible jawdropping intro David Baker's youtube briefs here are pretty cool:

https://www.youtube.com/watch?v=ZrAwWx7meTk

[SanderSantema]

I'm no expert, but I believe it's indeed what they're already doing: https://en.wikipedia.org/wiki/Genetically_modified_bacteria#...

But if I could make a guess I'd say that it in theory it might be relatively straightforward or easy to do but it's probably a lot harder in practice. That's often the case anyways.

[joyj2nd]

Short answer: Yes

Long answer: No. It would be an incredibly complex undertaking.

[heurifk]

Normal cells also use RNA during protein synthesis. Why doesn't remdesivir disrupt that too and kills healthy cells?

[est31]

There is no RNA cloning machinery in our cells. The RNA is instead copied from the DNA in the nucleus. Viruses like the coronavirus actually bring their own RNA cloning machinery that's assembled by the cell. Remdesivir only blocks the RNA cloning proteins of the virus.

[rocqua]

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?

[rwmj]

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

[lisk1]

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

[malwarebytess]

sounds like we should get on it

[vikramkr]

Yep. This is the same drug they tried to deploy against Ebola, and that's why they think itll be useful for such a wildly different drug virus here as well