GS-441524

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 and is widely used despite no official FDA approval due to Gilead's refusal to license this drug for veterinary use.[2][3][4][5]

GS-441524
Legal status
Legal status
  • US: Investigational drug
Identifiers
IUPAC name
  • (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
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC12H13N5O4
Molar mass291.267 g·mol−1
3D model (JSmol)
SMILES
  • C1=C2C(=NC=NN2C(=C1)[C@]3([C@@H]([C@@H]([C@H](O3)CO)O)O)C#N)N
InChI
  • 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

Use and research

Since FIP is usually fatal and there are no approved treatments available, GS-441524 has reportedly been sold 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][6] and even in more complicated forms of FIP such as those with multisystemic or neurological involvement.[7]

GS-441524 is either similar to or more potent than remdesivir against SARS-CoV-2 in cell culture,[8] with some researchers arguing that GS-441524 would be better than remdesivir for the treatment of COVID-19.[2][9][10][11] 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).[12] 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,[13] suggesting that GILEAD was not doing so for financial motives related to the longer intellectual property lifespan of Remdesivir. Direct efficacy against SARS-CoV-2 was demonstrated in a mouse model of COVID-19.[14] 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.[15]

GS-441524 is sold as a research chemical in very high purity (>99% by NMR and HPLC) by a number of suppliers including MedKoo, Selleckchem , MedChemExpress and TargetMol. Such sales for research purposes do not constitute patent infringements which was affirmed by a 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. Such chemicals, like any chemicals, may however be administered to patients at an individual clinician's discretion in practice (not as part of a formal trial); however harms resulting from such use are not as well legally protected from malpractice claims as is use of approved ethical pharmaceutical drugs.

GS-441524 has been directly administered in a healthy human,[16] with highest plasma concentrations of 12 uM reached, which is >10 times the concentration required for activity against SARS-CoV-2 in culture.

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.[17][18][19]

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.[20] 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.[21]

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.

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][7] 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.[7][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.[9][10][22]

See also

References
  1. "Veterinary advancements in managing Feline Infectious Peritonitis (FIP) in cats". Australian Veterinary Association Ltd. 19 February 2021.
  2. Westgate J (7 May 2020). "Vet science 'being ignored' in quest for COVID-19 drug". vet times. Retrieved 6 July 2020.
  3. 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. 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. 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. Burns K (15 January 2020). "FIP drugs continue to show promise, while being sold on black market". JAVMAnews. Retrieved 2 May 2020.
  7. Izes, Aaron M; Yu, Jane; Norris, Jacqueline M; Govendir, Merran (13 November 2020). "Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats". Veterinary Quarterly. 40 (1): 322–330. doi:10.1080/01652176.2020.1845917. PMC 7671703.
  8. 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.
  9. 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.
  10. Yan VC, Muller FL (14 May 2020). "Gilead should ditch remdesivir and focus on its simpler and safer ancestor". Statnews. Retrieved 5 July 2020.
  11. Siebenand S (15 April 2020). "Remdesivir-Metabolit noch schärfere Waffe gegen Covid-19?". Pharmazeutische Zeitung. Retrieved 6 July 2020.
  12. "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.
  13. "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.
  14. Li Y, Cao L, Li G, Cong F, Li Y, Sun J, et al. (February 2021). "Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models". Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.0c01929. PMC 7875336. PMID 33523654.
  15. 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:10.1101/2020.11.01.363812v1.
  16. Clinical trial number NCT04859244 for "First-in-Human Study of Orally Administered GS-441524 for COVID-19" at ClinicalTrials.gov
  17. 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): 381–5. doi:10.1038/nature17180. PMC 5551389. PMID 26934220.
  18. 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.
  19. 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.
  20. WP:CALC
  21. "GS-441524 Studies". National Center for Advancing Translational Sciences (NCATS). 21 April 2021.
  22. 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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