GC376

GC376 is a broad-spectrum antiviral medication under development by the biopharmaceutical company Anivive Lifesciences for therapeutic uses in humans and animals.[1] Anivive licensed the exclusive worldwide patent rights to GC376 from Kansas State University.[2] As of 2020, GC376 is being investigated as treatment for COVID-19.[3] GC376 shows activity against many human and animal viruses including coronavirus and norovirus;[4] the most extensive research has been multiple in vivo studies in cats treating a coronavirus which causes deadly feline infectious peritonitis.[5] Other research supports use in porcine epidemic diarrhea virus.[6]

GC376
Legal status
Legal status
  • US: Investigational drug
Identifiers
IUPAC name
  • sodium (2S)-1-hydroxy-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC21H30N3NaO8S
Molar mass507.53 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)C[C@@H](C(=O)N[C@@H](CC1CCNC1=O)C(O)S(=O)(=O)[O-])NC(=O)OCC2=CC=CC=C2.[Na+]
InChI
  • InChI=1S/C21H31N3O8S.Na/c1-13(2)10-16(24-21(28)32-12-14-6-4-3-5-7-14)19(26)23-17(20(27)33(29,30)31)11-15-8-9-22-18(15)25;/h3-7,13,15-17,20,27H,8-12H2,1-2H3,(H,22,25)(H,23,26)(H,24,28)(H,29,30,31);/q;+1/p-1/t15?,16-,17-,20?;/m0./s1
  • Key:BSPJDKCMFIPBAW-JPBGFCRCSA-M

COVID-19
Crystal structure of the PEDV 3CLpro in complex with GC376.[6]

Since GC376 shows broad-spectrum activity against coronavirus,[7] early on during the pandemic of 2020 it was suggested as a potential treatment for COVID-19.[8] In response to the crisis, researchers at the University of Arizona published in vitro research indicating GC376 is highly active against 3CLpro in SARS-CoV-2 (the coronavirus which causes COVID-19).[9] Another group of virologists at the University of Alberta lead by D. Lorne Tyrrell then released a separate publication confirming GC376's activity against 3CLpro in SARS-CoV-2 and also indicating GC376 had a potent antiviral effect.[10] The next day, Columbia University's Zuckerman Institute hosted a COVID-19 Virtual Symposium which released research led by David Ho and characterized GC376 as "the most promising" protease inhibitor under investigation in Ho's lab because GC376 was the "most potent" and reached "complete viral inhibition" in a culture of cells infected with SARS-CoV-2.[3]

Pharmacology

Pharmacodynamics

GC376 is a protease inhibitor. It blocks the 3CLpro, a protease common to many (+)ssRNA viruses, thereby preventing the viral polyprotein from maturing into its functional parts. Chemically, GC376 is the bisulfite adduct of an aldehyde GC373 and it behaves as a prodrug for that compound. This aldehyde forms a covalent bond with the cysteine-144 residue at the protease's active site, giving a monothioacetal and blocking the enzyme's normal function.[6][10]

See also

References
  1. "Anivive". www.anivive.com. Retrieved 2020-05-14.
  2. "Anivive licenses antiviral drug for fatal cat disease". www.k-state.edu. September 20, 2018. Retrieved 2020-05-14.{{cite web}}: CS1 maint: url-status (link)
  3. Brent Stockwell, COVID-19 Virtual Symposium May 6, 2020, retrieved 2020-05-14
  4. Takahashi D, Kim Y, Lovell S, Prakash O, Groutas WC, Chang KO (December 2013). "Structural and inhibitor studies of norovirus 3C-like proteases". Virus Research. 178 (2): 437–44. doi:10.1016/j.virusres.2013.09.008. PMC 3840063. PMID 24055466.
  5. Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, et al. (April 2018). "Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis". Journal of Feline Medicine and Surgery. 20 (4): 378–392. doi:10.1177/1098612X17729626. PMC 5871025. PMID 28901812.
  6. Ye G, Wang X, Tong X, Shi Y, Fu ZF, Peng G (February 2020). "Structural Basis for Inhibiting Porcine Epidemic Diarrhea Virus Replication with the 3C-Like Protease Inhibitor GC376". Viruses. 12 (2): 240. doi:10.3390/v12020240. PMC 7077318. PMID 32098094.
  7. Pillaiyar T, Meenakshisundaram S, Manickam M (April 2020). "Recent discovery and development of inhibitors targeting coronaviruses". Drug Discovery Today. 25 (4): 668–688. doi:10.1016/j.drudis.2020.01.015. PMC 7102522. PMID 32006468.
  8. Morse JS, Lalonde T, Xu S, Liu WR (March 2020). "Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV". ChemBioChem. 21 (5): 730–738. doi:10.1002/cbic.202000047. PMC 7162020. PMID 32022370.
  9. Ma, Chunlong; Sacco, Michael D.; Hurst, Brett; Townsend, Julia A.; Hu, Yanmei; Szeto, Tommy; Zhang, Xiujun; Tarbet, Bart; Marty, Michael T.; Chen, Yu; Wang, Jun (20 April 2020). "Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease". bioRxiv. doi:10.1101/2020.04.20.051581. PMC 7263507. PMID 32511378. S2CID 216145410.
  10. Vuong, Wayne; Khan, Muhammad Bashir; Fischer, Conrad; Arutyunova, Elena; Lamer, Tess; Shields, Justin; Saffran, Holly A.; McKay, Ryan T.; van Belkum, Marco J.; Joyce, Michael A.; Young, Howard S.; Tyrrell, D. Lorne; Vederas, John C.; Lemieux, M. Joanne (December 2020). "Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication". Nature Communications. 11 (1): 4282. doi:10.1038/s41467-020-18096-2. PMC 7453019. PMID 32855413. S2CID 218551888.


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