GS-441524

Since untreated feline infectious peritonitis (FIP) is fatal in almost all cases{{Cite web |title=Feline Infectious Peritonitis |url=https://vcahospitals.com/know-your-pet/feline-infectious-peritonitis |access-date=2023-10-15 |website=Vca |publisher=VCA Animal Hospitals |language=en}} 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,{{cite news| vauthors = Burns K |date=15 January 2020|title=FIP drugs continue to show promise, while being sold on black market|url=https://www.avma.org/javma-news/2020-01-15/fip-drugs-continue-show-promise-while-being-sold-black-market|work=JAVMAnews|access-date=2 May 2020}} and even in more complicated forms of FIP such as those with multisystemic or neurological involvement.{{cite journal | vauthors = Izes AM, Yu J, Norris JM, Govendir M | title = Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats | journal = The Veterinary Quarterly | volume = 40 | issue = 1 | pages = 322–330 | date = December 2020 | pmid = 33138721 | pmc = 7671703 | doi = 10.1080/01652176.2020.1845917 }} 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.{{Cite web |title=Successful Feline Infectious Peritonitis Treatment with Remdesivir at the RVC |url=https://www.rvc.ac.uk/clinical-connections/successful-feline-infectious-peritonitis-treatment-with-remdesivir |access-date=2023-10-15 |website=www.rvc.ac.uk}}{{Cite web |title=FIP Antivirals {{!}} Fight FIP |url=https://blogs.cornell.edu/fightfip/fip-antivirals/ |access-date=2023-10-15 |website=blogs.cornell.edu |publisher=Whittaker Lab - Cornell University |language=en-US}}{{cite journal | vauthors = Jones S, Novicoff W, Nadeau J, Evans S | title = Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for at-Home Treatment of Feline Infectious Peritonitis | journal = Animals | volume = 11 | issue = 8 | pages = 2257 | date = July 2021 | pmid = 34438720 | pmc = 8388366 | doi = 10.3390/ani11082257 | doi-access = free }}

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,{{Efn||name=NLnote|group=lower-alpha}} and the United Kingdom. As of June 2024, the medication is available in the U.S.{{Cite web |title=FIP treatment GS-441524 - now available in the U.S. {{!}} Cornell University College of Veterinary Medicine |url=https://www.vet.cornell.edu/departments-centers-and-institutes/cornell-feline-health-center/health-information/feline-health-topics/fip-treatment-gs-441524-now-available-us |access-date=2025-03-27 |website=www.vet.cornell.edu |language=en}}

GS-441524 is either similar to or more potent than remdesivir against SARS-CoV-2 in cell culture,{{cite journal | vauthors = Pruijssers AJ, George AS, Schäfer A, Leist SR, Gralinksi LE, Dinnon KH, Yount BL, Agostini ML, Stevens LJ, Chappell JD, Lu X, Hughes TM, Gully K, Martinez DR, Brown AJ, Graham RL, Perry JK, Du Pont V, Pitts J, Ma B, Babusis D, Murakami E, Feng JY, Bilello JP, Porter DP, Cihlar T, Baric RS, Denison MR, Sheahan TP | display-authors = 6 | title = Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice | journal = Cell Reports | volume = 32 | issue = 3 | pages = 107940 | date = July 2020 | pmid = 32668216 | pmc = 7340027 | doi = 10.1016/j.celrep.2020.107940 | doi-access = free }} with some researchers arguing that GS-441524 would be better than remdesivir for the treatment of COVID-19.{{cite journal | vauthors = Yan VC, Muller FL | title = Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment | journal = ACS Medicinal Chemistry Letters | volume = 11 | issue = 7 | pages = 1361–1366 | date = July 2020 | pmid = 32665809 | pmc = 7315846 | doi = 10.1021/acsmedchemlett.0c00316 | s2cid = 220056568 }}{{cite news| vauthors = Yan VC, Muller FL |date=14 May 2020|title=Gilead should ditch remdesivir and focus on its simpler and safer ancestor|url=https://www.statnews.com/2020/05/14/gilead-should-ditch-remdesivir-and-focus-on-its-simpler-safer-ancestor/|work=Statnews|access-date=5 July 2020}}{{cite news| vauthors = Siebenand S |date=15 April 2020|title=Remdesivir-Metabolit noch schärfere Waffe gegen Covid-19?|url=https://www.pharmazeutische-zeitung.de/remdesivir-metabolit-noch-schaerfere-waffe-gegen-covid-19-117613/|work=Pharmazeutische Zeitung|access-date=6 July 2020}} 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).{{cite web|url=https://www.fda.gov/media/137566/download|title=Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Veklrty® (remdesivir)|author=|date=July 2020|website=fda.gov|publisher=Food and Drug Administration|access-date=15 August 2020}} 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,{{cite press release|author=|date=4 August 2020|title=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|url=https://www.citizen.org/article/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/|publisher=Public Citizen|agency=Public Citizen|access-date=15 August 2020}} 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.{{cite journal | vauthors = Imran M, Alshrari AS, Asdaq SM | title = Trends in the development of remdesivir based inventions against COVID-19 and other disorders: A patent review | journal = Journal of Infection and Public Health | volume = 14 | issue = 8 | pages = 1075–1086 | date = August 2021 | pmid = 34243049 | pmc = 8236076 | doi = 10.1016/j.jiph.2021.06.013 }} Direct efficacy against SARS-CoV-2 was demonstrated in a mouse model of COVID-19.{{cite journal | vauthors = Li Y, Cao L, Li G, Cong F, Li Y, Sun J, Luo Y, Chen G, Li G, Wang P, Xing F, Ji Y, Zhao J, Zhang Y, Guo D, Zhang X | display-authors = 6 | title = Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models | journal = Journal of Medicinal Chemistry | volume = 65 | issue = 4 | pages = 2785–2793 | date = February 2022 | pmid = 33523654 | pmc = 7875336 | doi = 10.1021/acs.jmedchem.0c01929 }}

GS-441524 has been directly administered in a healthy human,{{ClinicalTrialsGov|NCT04859244|First-in-Human Study of Orally Administered GS-441524 for COVID-19}} with highest plasma concentrations of 12 uM reached, which is >10 times the concentration required for activity against SARS-CoV-2 in culture.

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.{{cite journal | vauthors = Russo AA, Johnson J | title = Research use exemptions to patent infringement for drug discovery and development in the United States | journal = Cold Spring Harbor Perspectives in Medicine | volume = 5 | issue = 2 | pages = a020933 | date = October 2014 | pmid = 25359549 | pmc = 4315915 | doi = 10.1101/cshperspect.a020933 }} 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.

{{main|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.{{cite journal | vauthors = Yin W, Luan X, Li Z, Xie Y, Zhou Z, Liu J, Gao M, Wang X, Zhou F, Wang Q, Wang Q | title = Structural basis for repurpose and design of nucleoside drugs for treating COVID-19 | journal = bioRxiv | date = January 2020 | doi = 10.1101/2020.11.01.363812 | s2cid = 226263471 }}{{cite journal | vauthors = Cao Z, Gao W, Bao H, Feng H, Mei S, Chen P, Gao Y, Cui Z, Zhang Q, Meng X, Gui H, Wang W, Jiang Y, Song Z, Shi Y, Sun J, Zhang Y, Xie Q, Xu Y, Ning G, Gao Y, Zhao R | display-authors = 6 | title = VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19 | journal = The New England Journal of Medicine | volume = 388 | issue = 5 | pages = 406–417 | date = February 2023 | pmid = 36577095 | pmc = 9812289 | doi = 10.1056/NEJMoa2208822 }} 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.{{Cite web | vauthors = Devarasetti H |date=2023-01-30 |title=China's NMPA conditionally approves two oral drugs for Covid-19 |url=https://www.pharmaceutical-technology.com/news/china-nmpa-oral-drugs-covid-19/ |access-date=2023-02-04 |website=Pharmaceutical Technology |language=en-US}}

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.{{cn|date=November 2022}}

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.{{cite journal | vauthors = Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen SS, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S | display-authors = 6 | title = Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys | journal = Nature | volume = 531 | issue = 7594 | pages = 381–385 | date = March 2016 | pmid = 26934220 | pmc = 5551389 | doi = 10.1038/nature17180 | bibcode = 2016Natur.531..381W }}{{cite journal | vauthors = Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS | display-authors = 6 | title = Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses | journal = Science Translational Medicine | volume = 9 | issue = 396 | pages = eaal3653 | date = June 2017 | pmid = 28659436 | pmc = 5567817 | doi = 10.1126/scitranslmed.aal3653 }}{{cite journal | vauthors = Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, van Doremalen N, Leighton I, Kwe Yinda C, Pérez-Pérez L, Okumura A, Lovaglio J, Hanley PW, Saturday G, Bosio CM, Anzick S, Barbian K, Cihlar T, Martens C, Scott DP, Munster VJ, de Wit E | display-authors = 6 | title = Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2 | journal = bioRxiv | pages = 2020.04.15.043166 | date = April 2020 | pmid = 32511319 | pmc = 7239049 | doi = 10.1101/2020.04.15.043166 }}

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).{{CN|date=November 2021}} 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. WP:CALC More recent data releases from NCATS shows that GS-441524 is tolerated at 1000 mg/kg in dogs with a maximum plasma concentration (C_max) of nearly 100 μM, or about 100-fold higher than the concentrations required for activity against the virus in cell culture.{{cite web | title = GS-441524 Studies | date = 21 April 2021 | url = https://opendata.ncats.nih.gov/covid19/GS-441524 | work = National Center for Advancing Translational Sciences (NCATS) }}

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.{{cn|date=November 2022}}

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.

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. 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.

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.{{cite web | vauthors = Giovinco J | date = 14 February 2020 | work = Fox 5 | location = New York | title = Feline coronavirus treatment could stop spread of COVID-19 in humans, doctor says | url = https://www.fox5ny.com/news/feline-coronavirus-treatment-could-stop-spread-of-covid-19-in-humans-doctor-says}}

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