In vitro: GC376 covalently binds to Cys 139, Cys 147, and Cys 144 of NV 3CLpro, PV 3Cpro, and TGEV 3CLpro, respectively. GC376 is 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 is less sensitive to GC376, with IC50 of 35 μM. GC376 shows no or weak effectiveness against the replication of HAV in cells. Proteases from NV, MD145 or MNV-1 are inhibited by GC376 with a similar potency. The IC50 values of GC376 against 3CLpro from NV, MD145, and MNV-1 are comparable among tested viruses. GC376 effectively inhibits the replication of NPI52-resistant viruses in cell culture as wild-type viruses, indicating that the mutation does not confer cross-resistance to GC376.
In vivo: GC376 exhibits favorable bioavailability and safety in cats. GC376 is rapidly absorbed after s.c. administration and the peak plasma level is reached within 2 hr after injection. The mean plasma drug concentrations remains above the 50% effective concentration (EC50) value of the aldehyde form of GC376 (8 ng/mL) for 18 hrs post injection. Virus infected cats shows improvement in attitude and resolution of fever. The profound absolute lymphopenia observed in all cats prior to antiviral treatment also returns to normal before the next blood testing one week later.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10 mM in DMSO|
Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis.
Pedersen NC, et al. J Feline Med Surg. 2017 Sep 1;1098612X17729626. PMID: 28901812.
Broad-spectrum antivirals against 3C or 3C-like proteases of picornaviruses, noroviruses, and coronaviruses.
Kim Y, et al. J Virol. 2012 Nov;86(21):11754-62. PMID: 22915796.
Brevianamide F belongs to a class of naturally occurring 2,5-diketopiperazines.
Telotristat ethyl, also known as LX1606, is an oral serotonin synthesis inhibitor or peripheral tryptophan hydroxylase (TPH) inhibitor.
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