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Formula | C12H13N5O4 |
Molar mass | 291.267 g·mol−1 |
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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.
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).
Since untreated feline infectious peritonitis (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]
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.
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.
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]
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 ]
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 ]
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]
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]
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 before it reaches the site of action or systemic circulation. The effect is most associated with orally administered medications, but some drugs still undergo first-pass metabolism even when delivered via an alternate route. During this metabolism, drug is 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; however, 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). First-pass metabolism is not to be confused with Phase I metabolism, which is a separate process.
Feline infectious peritonitis (FIP) is a common and aberrant immune response in cats to infection with feline coronavirus (FCoV).
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).
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.
The ProTide technology is a prodrug approach used in molecular biology and drug design. It is designed to deliver nucleotide analogues into the cell. This technology was invented by Professor Chris McGuigan from the School of Pharmacy and Pharmaceutical Sciences at Cardiff University in the early 1990s. ProTides form a critical part of antiviral drugs such as sofosbuvir, tenofovir alafenamide, and remdesivir.
MK-608 is an antiviral drug, an adenosine analog. It was originally developed by Merck & Co. as a treatment for hepatitis C, but despite promising results in animal studies, it was ultimately unsuccessful in clinical trials. Subsequently it has been widely used in antiviral research and has shown activity against a range of viruses, including Dengue fever, tick-borne encephalitis virus, poliovirus, and most recently Zika virus, in both in vitro and animal models. Since it has already failed in human clinical trials previously, it is unlikely MK-608 itself will be developed as an antiviral medication, but the continuing lack of treatment options for these emerging viral diseases means that much research continues using MK-608 and related antiviral drugs.
NITD008 is an antiviral drug classified as an adenosine analog. It was developed as a potential treatment for flavivirus infections and shows broad spectrum antiviral activity against many related viruses such as dengue virus, West Nile virus, yellow fever virus, Powassan virus, hepatitis C virus, Kyasanur Forest disease virus, Omsk hemorrhagic fever virus, and Zika virus. However, NITD008 proved too toxic in pre-clinical animal testing to be suitable for human trials, but it continues to be used in research to find improved treatments for emerging viral diseases.
Remdesivir, sold under the brand name Veklury, is a broad-spectrum antiviral medication developed by the biopharmaceutical company Gilead Sciences. It is administered via injection into a vein. During the COVID‑19 pandemic, remdesivir was approved or authorized for emergency use to treat COVID‑19 in numerous countries.
Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.
COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research, with 419 potential COVID-19 drugs in clinical trials, as of April 2021.
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.
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.
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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.
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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.
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.