GS-441524

Key takeaways

GS-441524 belongs to science; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect GS-441524 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of GS-441524 from memory before moving on to harder problems.

Reference excerpt

GS-441524 is a nucleoside analogue antiviral drug which was developed by Gilead Sciences. It is the main plasma metabolite of the antiviral prodrug remdesivir, and has a half-life of around 24 hours in human patients. Remdesivir and GS-441524 were both found to be effective in vitro against feline coronavirus strains responsible for feline infectious peritonitis (FIP), a lethal systemic disease affecting domestic cats. Remdesivir was never tested in cats (though some vets now offer it), but GS-441524 has been found to be effective treatment for FIP. It is widely used despite no official FDA approval due to Gilead's refusal to license this drug for veterinary use. In several countries oral GS-441524 tablets (and injectable remdesivir) became legally available to vets for the treatment of FIP in cats, for example Australia, the Netherlands, and the United Kingdom. Besides remdesivir, other prodrugs include obeldesivir (Gilead Sciences, Phase III) and deuremidevir (Vigonvita/Junshi, conditional approval in China).

Use and research

Feline infectious peritonitis Since untreated feline infectious peritonitis (FIP) is fatal in almost all cases and in most countries there are no approved treatments available, GS-441524 has reportedly been sold illegally worldwide on the black market and used by pet owners to treat affected cats, although Gilead Sciences has refused to license the drug for veterinary use. Its efficacy for this purpose has been conclusively demonstrated in multiple trials, including field trials, and even in more complicated forms of FIP such as those with multisystemic or neurological involvement. In naturally infected cats, a recovery rate of over 80% has been observed with GS-441524 treatment in several studies and in treatment programs in countries where the drug is legalised. As of 2023, oral GS-441524 tablets or capsules (and injectable remdesivir) became legally available to vets for the treatment of FIP in cats in Australia, the Netherlands, and the United Kingdom. As of June 2024, the medication is available in the U.S.

COVID-19 GS-441524 is either similar to or more potent than remdesivir against SARS-CoV-2 in cell culture, with some researchers arguing that GS-441524 would be better than remdesivir for the treatment of COVID-19. Specific advantages cited include ease of synthesis, lower kidney and hepatotoxicity, as well as potential for oral delivery (which is precluded of remdesivir because of poor hepatic stability and first pass metabolism). The public health advocacy group, Public Citizen, in an open letter urged the DHHS and Gilead to investigate GS-441524 for the treatment of COVID-19, suggesting that Gilead was not doing so for financial motives related to the longer intellectual property lifespan of remdesivir, whose patents expire no sooner than 2035. Direct efficacy against SARS-CoV-2 was demonstrated in a mouse model of COVID-19. GS-441524 has been directly administered in a healthy human, with highest plasma concentrations of 12 uM reached, which is >10 times the concentration required for activity against SARS-CoV-2 in culture.

USA regulations GS-441524 is sold as a research chemical in very high purity (>99% by NMR and HPLC) by a number of suppliers. Such sales for research purposes do not constitute patent infringements which was affirmed by a U.S. Supreme Court decision. However, despite the high purity, under FDA regulations, such chemicals are not allowed for clinical trials since their manufacture is not performed under FDA cGMP certified conditions.

Deuremidevir

A deuterium modified version of GS-441524 has been produced and has shown pre-clinical efficacy in both cell culture and mouse models by a team including members of Wuhan Institute of Virology. A subsidiary of Shanghai Junshi Biosciences received conditional approval for VV116, now named deuremidevir, to treat adults with COVID-19 from China's National Medical Products Administration on January 30, 2023.

Pharmacology

Pharmacodynamics GS-441524 nucleoside is phosphorylated by nucleoside kinases (probably adenosine kinase (ADK), which is the enzyme that phosphorylates the structurally similar ribavirin), and then phosphorylated again by nucleoside-diphosphate kinase (NDK) to the active nucleotide triphosphate form. The triphosphate of GS-441524, GS-443902, is also the bioactive anti-viral agent generated by remdesivir, but is generated by a different biochemical mechanism from the later.

Pharmacokinetics GS-441524 is a 1'-cyano-substituted adenosine analogue. It is remdesivir's predominant metabolite circulating in the serum due to rapid hydrolysis (half life less than 1 hour) followed by dephosphorylation. In response to the letter from Public Citizen, National Institutes of Health's drug discovery arm, National Center for Advancing Translational Sciences (NCATS), has started systematic Investigational New Drug enabling experiments including pharmacokinetics in multiple pre-clinical species, and also (in October) in humans (results not yet published). Oral bioavailability was found to be excellent in dogs, good in mice, but modest in cynomolgus non-human primates. Prediction of human oral bioavailability from pre-clinical data is more art than science, and relies on modeling data from multiple species. Taking as reference point the clinical and pre-clinical data of other nucleoside analogues, human oral bioavailability of GS-441524 is expected to fall somewhere in between that seen in dog as a high point and that seen in non-human primates. Since GS-441524 has a bit less than half the molecular weight of remdesivir, it will deliver as much active metabolite to the blood as the same dose of remdesivir (for example, 100 mg), even if human oral bioavailability is 50%, comparable to (for example) ribavirin. More recent data releases from NCATS shows that GS-441524 is tolerated at 1000 mg/kg in dogs with a maximum plasma concentration (Cmax) of nearly 100 μM, or about 100-fold higher than the concentrations required for activity against the virus in cell culture. The elimination half-life of GS-441524 is around 2 hours in cynomolgus, much shorter than the 24 hours reported in humans. The longer half life suggests once-a-day dosing if the drug is approved for human oral use.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with GS-441524

Start with the simplest possible case. Write down what GS-441524 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to GS-441524 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about GS-441524 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of GS-441524

In research: GS-441524 appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses GS-441524 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: GS-441524 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Antiviral drugs, Anti–RNA virus drugs, Nitriles, so understanding it makes those chapters shorter.
In everyday life: Look for GS-441524 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study GS-441524 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what GS-441524 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain GS-441524 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is GS-441524 in simple terms?

GS-441524 is a nucleoside analogue antiviral drug which was developed by Gilead Sciences. It is the main plasma metabolite of the antiviral prodrug remdesivir, and has a half-life of around 24 hours in human patients.

Why does GS-441524 matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study GS-441524?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on GS-441524.