Novel Broad-Spectrum Antivirals against Noroviruses, Picornaviruses and Coronaviruses

Reference Number: 11-13

Inventors: Kyeong-Ok Chang, Yunjeong Kim, William C Groutas

Description:

Many viruses in the picornavirus-like supercluster, including caliciviruses, picornaviruses, and coronaviruses, are important human and animal pathogens. These viruses include noroviruses, enteroviruses, poliovirus, foot-and-mouth disease virus, human rhinoviruses (cause of common cold), human coronavirus (another cause of common cold), transmissible gastroenteritis virus, murine hepatitis virus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus. A research team from Kansas State University, Wichita State University and the Ohio State University came together to develop novel therapeutics against these viruses. The group is currently funded through a NIH U01 with a specific aim of developing novel antiviral drugs. From their research, series of novel inhibitors targeting 3C or 3CL virus proteases, highly conserved among these viruses, were synthesized that have shown broad-spectrum activity against these viruses in cells and in vivo (norovirus).

Advantages:
  • Currently, there is no FDA-approved antiviral against picornaviruses, noroviruses or coronaviruses.
  • The wide applicability of the inhibitors shows a significant advancement in antiviral research and public health.
  • Series of compounds exhibit high efficacy with IC50 in nanomolar ranges with low cytotoxicity and have in vitro therapeutic indexes of >500.
  • In vivo testing using gnotobiotic pigs infected with human norovirus proved efficacy of the novel protease inhibitor.
Potential Applications:
  • Antiviral therapeutics for single or a wide range of viral infections.
    • Common cold (applicable to multiple strains of rhinoviruses and coronaviruses).
    • Noroviruses, a category B bioterrorism agent and the most common cause of viral gastroenteritis.
    • Other coronaviruses including severe acute respiratory syndrome coronavirus, feline infectious peritonitis virus, etc.
    • Picornaviruses including enterovirus 71 and coxsackieviruses, causes of foot and mouth disease and diverse spectrum of diseases.
Patent Status:
  • International Patent Protection (#14/377,123) filed in USA on March 27, 2014.
  • International Patent Protection (#12837222.4) filed in EPO on March 25, 2014.
  • International Patent Protection (#2,850,003) filed in Canada on March 25, 2014.

Kansas State University Research Foundation seeks to have discussions with companies that are interested in licensing and/or research collaborations.

Interested parties should contact:

Kansas State University Institute for Commercialization (KSU-IC)
2005 Research Park Circle Manhattan, KS 66502
Tel: 785-532-3900 Fax: 785-532-3909
E-Mail: ic@k-state.edu

Results:

FIG 1. Crystal structures of apo-NV 3CLpro and NV 3CLpro in complex with GC376. (A) noncrystallographic symmetry (NCS) dimer of NV 3CLpro showing chain A (blue) and chain B (magenta). (B) NCS dimer of apo-NV 3CLpro showing chain A (magenta) and chain B (blue) superimposed with the GC376-bound form showing chain A (cyan) and chain B (green). (C) Hydrogen bonding (dashed lines) interactions between NV 3CLpro (cyan) and GC376 (grey)

TABLE 1. Effects of GC373, GC375, and GC376 on replication of SELECTED viruses in cell culture as determined by the TCID50 method or real-time qRT-PCR.

 Inhibition (IC50 [µM]) against virus (mean ± SEM) a
 CalicivirusesCoronaviruses Picornaviruses
DrugNV repliconFIPV229EEV71CVHRV18HRV51HRV68
GC3730.20.30.211.10.21.11.81.6
GC3752.81.50.2515.20.10.090.080.07
GC3760.30.20.1510.30.21.21.50.8
Rupintrivir2.310.30.30.50.030.030.020.04
a SEM, standard error of the mean. NV, norovirus; FIPV, feline infectious peritonitis virus; 229E, human coronavirus 229E; EV71, Enterovirus 71; CV, Coxsackievirus B2; HRV 18, 51, and 68, human rhinovirus strains 18, 51, and 68. Rupintrivir was included as a control.

TABLE 2. Summary of results for treatment with GC376 in gnotobiotic pigs. On day 1 after oral inoculation with 8.0×109 genome equivalent of human norovirus (GII.12 HS206), 7-day-old piglets (body weight 1-1.5 kg) were treated therapeutically orally with 100 mg/kg of compound B (GC376) once a day for 5 days.

GroupMean log10 virus titer/rectal swab (GE/ml) (SEM)
 Tx at PIDs 1-5Tx at PIDs 6-14Overall duration of virus shedding at PIDs 1-14
GC3765.28 (0.13) A5.11 (0.10) B5.17 (0.08) B
DMSO5.21 (0.19) A5.85 (0.09) A5.62 (0.11) A
One-way ANOVA and the Tukey’s test were used for statistical analysis, and different capital letters denote significant differences among groups.

Summary:At PID 6-14 after treatment was discontinued, the gnotobiotic pigs treated with GC376 had significantly lower fecal viral RNA titers as compared to positive control pigs treated with 30% DMSO (vehicle).