GS-441524

Last updated
GS-441524
GS-441524 skeletal.svg
Legal status
Legal status
  • AU:Yes
  • UK:Yes
  • US:Investigational drug
  • EU:No,legal treatment available in the Netherlands
Identifiers
  • (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C12H13N5O4
Molar mass 291.267 g·mol−1
3D model (JSmol)
  • C1=C2C(=NC=NN2C(=C1)[C@]3([C@@H]([C@@H]([C@H](O3)CO)O)O)C#N)N
  • InChI=1S/C12H13N5O4/c13-4-12(10(20)9(19)7(3-18)21-12)8-2-1-6-11(14)15-5-16-17(6)8/h1-2,5,7,9-10,18-20H,3H2,(H2,14,15,16)/t7-,9-,10-,12+/m1/s1
  • Key:BRDWIEOJOWJCLU-LTGWCKQJSA-N

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 [1] ), but GS-441524 has been found to be effective treatment for FIP.

Contents

It is widely used despite no official FDA approval due to Gilead's refusal to license this drug for veterinary use. [2] [3] [4] [5] 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, [6] the Netherlands, [7] [lower-alpha 1] and the United Kingdom. [6]

Besides remdesivir, other prodrugs include obeldesivir (Gilead Sciences, Phase III) and deuremidevir (Vigonvita/Junshi, conditional approval in China).

Use and research

Feline Infectious Peritonitis (FIP)

Since untreated FIP is fatal in almost all cases [9] 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, [2] [3] [10] and even in more complicated forms of FIP such as those with multisystemic or neurological involvement. [11] 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. [6] [12] [13] [14]

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, [6] the Netherlands, [7] [lower-alpha 1] and the United Kingdom. [6]

COVID-19

GS-441524 is either similar to or more potent than remdesivir against SARS-CoV-2 in cell culture, [15] with some researchers arguing that GS-441524 would be better than remdesivir for the treatment of COVID-19. [2] [16] [17] [18] 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). [19] 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, [20] 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. [21] Direct efficacy against SARS-CoV-2 was demonstrated in a mouse model of COVID-19. [22]

GS-441524 has been directly administered in a healthy human, [23] 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. [24] 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. [25] [26] 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. [27]

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.[ citation needed ]

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. [28] [29] [30]

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).[ citation needed ] 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. [31] 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. [32]

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.[ citation needed ]

Mechanism of action

Intracellular triple-phosphorylation of GS-441524 yields its active 1'-cyano-substituted adenosine triphosphate analogue, which directly disrupts viral RNA replication by competing with endogenous NTPs for incorporation into nascent viral RNA transcripts and triggering delayed chain termination of RNA-dependent RNA polymerase. [4]

Tolerance

In vitro experiments in Crandell Rees feline kidney (CRFK) cells found GS-441524 was nontoxic at 100 µM concentrations, 100 times the dose effective at inhibiting FIPV replication in cultured CRFK cells and infected macrophages. [4] [11] Clinical trials in cats indicate the drug is well-tolerated, with the primary side effect being dermal irritation from the acidity of the injection mix. [11] [5]

Some researchers suggesting its utility as a treatment for COVID-19 have pointed out advantages over remdesivir, including lack of on-target liver toxicity, longer half-life and exposure (AUC) and much cheaper and simpler synthesis. [16] [17] [33]

See also

Notes

  1. 1 2 At the moment, legal treatment with GS-441524 in the Netherlands is only available through vets from the Veterinary medicine department of Utrecht University. The drug is made in the University pharmacy. After a successful trial period starting in June 2023, the drug will become legally available for FIP treatment in cats to all vets in the country. Remdesivir can be legally used for treatment by all vets in the Netherlands under the cascade, [8] since its approval for the use in human COVID-19 treatment.

Related Research Articles

<span class="mw-page-title-main">First pass effect</span> Phenomenon of drug metabolism

The first pass effect is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug, specifically when administered orally, before it reaches the site of action or systemic circulation. It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall. The liver is the major site of first pass effect; it can also occur in the lungs, vasculature or other metabolically active tissues in the body. Notable drugs that experience a significant first-pass effect are buprenorphine, chlorpromazine, cimetidine, diazepam, ethanol, imipramine, insulin, lidocaine, midazolam, morphine, pethidine, propranolol, and tetrahydrocannabinol (THC).

<span class="mw-page-title-main">Feline infectious peritonitis</span> Highly deadly disease that affects cats

Feline infectious peritonitis (FIP) is the name given to a common and aberrant immune response in cats to infection with feline coronavirus (FCoV).

<span class="mw-page-title-main">Atovaquone</span> Antimicrobial and antiprotozoan drug

Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of Pneumocystis jirovecii pneumonia (PCP).

Cerebellar hypoplasia (CH) is a neurological condition in which the cerebellum is smaller than usual or not completely developed. It has been reported in many animal species.

Feline coronavirus (FCoV) is a positive-stranded RNA virus that infects cats worldwide. It is a coronavirus of the species Alphacoronavirus 1, which includes canine coronavirus (CCoV) and porcine transmissible gastroenteritis coronavirus (TGEV). FCoV has two different forms: feline enteric coronavirus (FECV), which infects the intestines, and feline infectious peritonitis virus (FIPV), which causes the disease feline infectious peritonitis (FIP).

<span class="mw-page-title-main">Favipiravir</span> Experimental antiviral drug with potential activity against RNA viruses

Favipiravir, sold under the brand name Avigan among others, is an antiviral medication used to treat influenza in Japan. It is also being studied to treat a number of other viral infections, including SARS-CoV-2. Like the experimental antiviral drugs T-1105 and T-1106, it is a pyrazinecarboxamide derivative.

<span class="mw-page-title-main">Galidesivir</span> Antiviral drug

Galidesivir is an antiviral drug, an adenosine analog. It was developed by BioCryst Pharmaceuticals with funding from NIAID, originally intended as a treatment for hepatitis C, but subsequently developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease, as well as Zika virus. Currently, galidesivir is under phase 1 human trial in Brazil for coronavirus.

<span class="mw-page-title-main">Protide</span>

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<span class="mw-page-title-main">NITD008</span> Chemical compound

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<span class="mw-page-title-main">Remdesivir</span> Antiviral drug

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<span class="mw-page-title-main">COVID-19 drug development</span> Preventative and therapeutic medications for COVID-19 infection

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<span class="mw-page-title-main">GC376</span> Broad-spectrum antiviral medication

GC376 is a broad-spectrum antiviral medication under development by the biopharmaceutical company Anivive Lifesciences for therapeutic uses in humans and animals. Anivive licensed the exclusive worldwide patent rights to GC376 from Kansas State University. As of 2020, GC376 is being investigated as treatment for COVID-19. GC376 shows activity against many human and animal viruses including coronavirus and norovirus; the most extensive research has been multiple in vivo studies in cats treating a coronavirus which causes deadly feline infectious peritonitis. Other research supports use in porcine epidemic diarrhea virus.

Tomáš Cihlář is a Czech biochemist known for his role in the development of remdesivir. A specialist in virology, Cihlář holds the positions of Senior Director, Biology, and Vice-President at American pharmaceutical company Gilead Sciences. As a student, Cihlář assisted fellow biochemist Antonín Holý in developing Viread, the primary drug used to fight HIV infection.

<span class="mw-page-title-main">Molnupiravir</span> Antiviral medication

Molnupiravir, sold under the brand name Lagevrio, is an antiviral medication that inhibits the replication of certain RNA viruses. It is used to treat COVID-19 in those infected by SARS-CoV-2. It is taken by mouth.

<span class="mw-page-title-main">Nirmatrelvir</span> COVID-19 antiviral medication

Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3C-like protease inhibitor. It is part of a nirmatrelvir/ritonavir combination used to treat COVID-19 and sold under the brand name Paxlovid.

<span class="mw-page-title-main">Lufotrelvir</span> Chemical compound

Lufotrelvir (PF-07304814) is an antiviral drug developed by Pfizer which acts as a 3CL protease inhibitor. It is a prodrug with the phosphate group being cleaved in vivo to yield the active agent PF-00835231. Lufotrelvir is in human clinical trials for the treatment of COVID-19, and shows good activity against COVID-19 including several variant strains, but unlike the related drug nirmatrelvir it is not orally active and must be administered by intravenous infusion, and so has been the less favoured candidate for clinical development overall.

<span class="mw-page-title-main">Bemnifosbuvir</span> Chemical compound

Bemnifosbuvir is an antiviral drug invented by Atea Pharmaceuticals and licensed to Roche for clinical development, a novel nucleotide analog prodrug originally developed for the treatment of hepatitis C. Bemnifosbuvir is the orally bioavailable hemisulfate salt of AT-511, which is metabolized in several steps to the active nucleotide triphosphate AT-9010, acting as an RNA polymerase inhibitor and thereby interfering with viral replication. Bemnifosbuvir has been researched for the treatment of coronavirus diseases such as that produced by SARS-CoV-2. It showed good results in early clinical trials but had inconsistent results at later stages, so the planned Phase 3 trials are being redesigned and results are not expected until late 2022.

<span class="mw-page-title-main">Obeldesivir</span> Oral COVID-19 drug

Obeldesivir is an isobutyric ester prodrug of GS-441524 made by Gilead Sciences that is currently in Phase III trials for the outpatient treatment of COVID-19 in high risk patients. The purpose of the isobutyric ester modification on obeldesivir is to improve the oral bioavailability of the parent nucleoside, GS-441524. Obeldesivir is hydrolyzed to its parent nucleoside, GS-441524, which is in turn converted to remdesivir-triphosphate (GS-443902) by a nucleoside kinase, adenylate kinase and nucleotide diphosphate kinase.

<span class="mw-page-title-main">Deuremidevir</span> Antiviral drug

Deuremidevir, also known as VV116, is an nucleoside analogue antiviral drug. It is administrated through oral tablets, which contain the hydrobromide salt of this drug.

References

  1. ↑ "Veterinary advancements in managing Feline Infectious Peritonitis (FIP) in cats". Australian Veterinary Association Ltd. 19 February 2021.
  2. 1 2 3 Westgate J (7 May 2020). "Vet science 'being ignored' in quest for COVID-19 drug". vet times. Retrieved 6 July 2020.
  3. 1 2 Zhang S (8 May 2020). "A Much-Hyped COVID-19 Drug Is Almost Identical to a Black-Market Cat Cure". The Atlantic. Retrieved 6 July 2020.
  4. 1 2 3 Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, et al. (June 2018). "The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies". Veterinary Microbiology. 219: 226–233. doi:10.1016/j.vetmic.2018.04.026. PMC   7117434 . PMID   29778200.
  5. 1 2 Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H (April 2019). "Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis". Journal of Feline Medicine and Surgery. 21 (4): 271–281. doi:10.1177/1098612X19825701. PMC   6435921 . PMID   30755068.
  6. 1 2 3 4 5 "Feline Infectious Peritonitis (FIP)". icatcare.org. International Cat Care . Retrieved 2023-10-15.
  7. 1 2 "Nu ook in Nederland behandeling voor katten met FIP". www.licg.nl (in Dutch). Landelijk InformatieCentrum Gezelschapsdieren (LICG). Retrieved 2023-10-15.
  8. ↑ "Cascade". cbg-meb.nl. Medicines Evaluation Board. 6 October 2018. Retrieved 2023-10-15.
  9. ↑ "Feline Infectious Peritonitis". Vca. VCA Animal Hospitals . Retrieved 2023-10-15.
  10. ↑ Burns K (15 January 2020). "FIP drugs continue to show promise, while being sold on black market". JAVMAnews. Retrieved 2 May 2020.
  11. 1 2 3 Izes AM, Yu J, Norris JM, Govendir M (December 2020). "Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats". The Veterinary Quarterly. 40 (1): 322–330. doi:10.1080/01652176.2020.1845917. PMC   7671703 . PMID   33138721.
  12. ↑ "Successful Feline Infectious Peritonitis Treatment with Remdesivir at the RVC". www.rvc.ac.uk. Retrieved 2023-10-15.
  13. ↑ "FIP Antivirals | Fight FIP". blogs.cornell.edu. Whittaker Lab - Cornell University . Retrieved 2023-10-15.
  14. ↑ Jones S, Novicoff W, Nadeau J, Evans S (July 2021). "Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for at-Home Treatment of Feline Infectious Peritonitis". Animals. 11 (8): 2257. doi: 10.3390/ani11082257 . PMC   8388366 . PMID   34438720.
  15. ↑ Pruijssers AJ, George AS, Schäfer A, Leist SR, Gralinksi LE, Dinnon KH, et al. (July 2020). "Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice". Cell Reports. 32 (3): 107940. doi: 10.1016/j.celrep.2020.107940 . PMC   7340027 . PMID   32668216.
  16. 1 2 Yan VC, Muller FL (July 2020). "Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment". ACS Medicinal Chemistry Letters. 11 (7): 1361–1366. doi:10.1021/acsmedchemlett.0c00316. PMC   7315846 . PMID   32665809. S2CID   220056568.
  17. 1 2 Yan VC, Muller FL (14 May 2020). "Gilead should ditch remdesivir and focus on its simpler and safer ancestor". Statnews. Retrieved 5 July 2020.
  18. ↑ Siebenand S (15 April 2020). "Remdesivir-Metabolit noch schärfere Waffe gegen Covid-19?". Pharmazeutische Zeitung. Retrieved 6 July 2020.
  19. ↑ "Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Veklrty® (remdesivir)". fda.gov. Food and Drug Administration. July 2020. Retrieved 15 August 2020.
  20. ↑ "Letter to Gilead and Senior Federal Health Officials Calling for Immediate Study of the Antiviral Drug GS-441524 as a Potential Treatment for COVID-19" (Press release). Public Citizen. Public Citizen. 4 August 2020. Retrieved 15 August 2020.
  21. ↑ Imran M, Alshrari AS, Asdaq SM (August 2021). "Trends in the development of remdesivir based inventions against COVID-19 and other disorders: A patent review". Journal of Infection and Public Health. 14 (8): 1075–1086. doi:10.1016/j.jiph.2021.06.013. PMC   8236076 . PMID   34243049.
  22. ↑ Li Y, Cao L, Li G, Cong F, Li Y, Sun J, et al. (February 2022). "Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models". Journal of Medicinal Chemistry. 65 (4): 2785–2793. doi:10.1021/acs.jmedchem.0c01929. PMC   7875336 . PMID   33523654.
  23. ↑ Clinical trial number NCT04859244 for "First-in-Human Study of Orally Administered GS-441524 for COVID-19" at ClinicalTrials.gov
  24. ↑ Russo AA, Johnson J (October 2014). "Research use exemptions to patent infringement for drug discovery and development in the United States". Cold Spring Harbor Perspectives in Medicine. 5 (2): a020933. doi:10.1101/cshperspect.a020933. PMC   4315915 . PMID   25359549.
  25. ↑ Yin W, Luan X, Li Z, Xie Y, Zhou Z, Liu J, Gao M, Wang X, Zhou F, Wang Q, Wang Q (January 2020). "Structural basis for repurpose and design of nucleoside drugs for treating COVID-19". bioRxiv. doi:10.1101/2020.11.01.363812. S2CID   226263471.
  26. ↑ Cao Z, Gao W, Bao H, Feng H, Mei S, Chen P, et al. (February 2023). "VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19". The New England Journal of Medicine. 388 (5): 406–417. doi:10.1056/NEJMoa2208822. PMC   9812289 . PMID   36577095.
  27. ↑ Devarasetti H (2023-01-30). "China's NMPA conditionally approves two oral drugs for Covid-19". Pharmaceutical Technology. Retrieved 2023-02-04.
  28. ↑ Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. (March 2016). "Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys". Nature. 531 (7594): 381–385. Bibcode:2016Natur.531..381W. doi:10.1038/nature17180. PMC   5551389 . PMID   26934220.
  29. ↑ Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. (June 2017). "Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses". Science Translational Medicine. 9 (396): eaal3653. doi:10.1126/scitranslmed.aal3653. PMC   5567817 . PMID   28659436.
  30. ↑ Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, et al. (April 2020). "Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2". bioRxiv: 2020.04.15.043166. doi:10.1101/2020.04.15.043166. PMC   7239049 . PMID   32511319.
  31. ↑ WP:CALC
  32. ↑ "GS-441524 Studies". National Center for Advancing Translational Sciences (NCATS). 21 April 2021.
  33. ↑ Giovinco J (14 February 2020). "Feline coronavirus treatment could stop spread of COVID-19 in humans, doctor says". Fox 5. New York.
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