GC376 is an inhibitor of 3C-like proteases (3CLpro) with IC50 values range from 0.49~4.35 μM.

GC376 was significantly effective against caliciviruses (NV and MNV-1), coronaviruses (TGEV, FIPV, MHV, 229E, and BCV), and picornaviruses (HRVs 18, 51, and 68, EV71, and PTV), with nanomolar or low micromolar IC50s, except for FCV and HAV. Interestingly, FCV was less sensitive to GC376, with IC50s of 35 μM, respectively [1].

GC376 was administered subcutaneously every 12 h at a dose of 15 mg/kg. Results Nineteen of 20 cats treated with GC376 regained outward health within 2 weeks of initial treatment. However, disease signs recurred 1-7 weeks after primary treatment and relapses and new cases were ultimately treated for a minimum of 12 weeks. Relapses no longer responsive to treatment occurred in 13 of these 19 cats within 1-7 weeks of initial or repeat treatment(s) [2].

The toxic dose for 50% cell death (TD50) for each compound was determined for the various cells used in this study. Confluent cells grown in 96-well plates were treated with various concentrations (1 to 500 μM) of each compound for 72 h. Cell cytotoxicity was measured by a CytoTox 96 nonradioactive cytotoxicity assay kit and crystal violet staining. The in vitro therapeutic index was calculated by dividing the TD50 by the IC50 [1].

GC376 was synthesized in a highly pure form and formulated at a concentration of 53 mg/ml in 10% ethanol and 90% polyethylene glycol 400, as described previously. GC376 was administered subcutaneously (SC) at a dosage of 15 mg/kg q12h SC, unless stated otherwise. The effective dosage for cats with experimentally induced FIP was 10 mg/kg/ q12h SC, but the dosage was raised to 15 mg/kg after the first cat (CT01) failed to respond to a lower dose of 10 mg/kg suggested by earlier pharmacokinetic studies. This was a clinical decision based on this one cat's response to treatment [2].

1416992-39-6

C21H30N3NaO8S

507.53

GC376 sodium

[1]Pedersen NC, et al. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg. 2018 Apr;20(4):378-392. [2]Theerawatanasirikul S, Kuo C J, Phecharat N, et al. Structural-based virtual screening and in vitro assays for small molecules inhibiting the feline coronavirus 3CL protease as a surrogate platform for coronaviruses[J]. Antiviral research,. 2020, 182: 104927. [3]Wang Y C, Yang W H, Yang C S, et al. Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug[J]. American Journal of Cancer Research. 2020, 10(8): 2535. [4]Kim Y, et al. Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses. J Virol. 2012 Nov;86(21):11754-62. [5]Fu L, Ye F, Feng Y, et al. Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nature communications. 2020, 11(1): 1-8.

[1]Bai Y, Ye F, Feng Y, et al. Structural basis for the inhibition of the SARS-CoV-2 main protease by the anti-HCV drug narlaprevir. Signal Transduction and Targeted Therapy. 2021, 6(1): 1-3 [2]Fu L, Ye F, Feng Y, et al Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease. Nature communications. 2020 Sep 4;11(1):4417. doi: 10.1038/s41467-020-18233-x. [3]Theerawatanasirikul S, Kuo C J, Phecharat N, et al. Structural-based virtual screening and in vitro assays for small molecules inhibiting the feline coronavirus 3CL protease as a surrogate platform for coronaviruses. Antiviral research, 2020, 182: 104927. [4]Herrmann A, Jungnickl D, Cordsmeier A, et al. Cloning of a Passage-Free SARS-CoV-2 Genome and Mutagenesis Using Red Recombination. International Journal of Molecular Sciences. 2021, 22(19): 10188. [5]Wang Y C, Yang W H, Yang C S, et al. Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug. American Journal of Cancer Research. 2020, 10(8): 2535

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