A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-alpha-2b and nucleoside analogues.
The novel small molecule, BIT225 (N-[5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl]-guanidine: CAS No. 917909-71-8), was initially identified using a screening strategy designed to detect inhibitors of Hepatitis C virus (HCV) p7 ion channel activity. Here we report that BIT225 has potent stand-alone antiviral activity against the HCV model pestivirus bovine viral diarrhea virus (BVDV) with an IC(50) of 314nM. Combinations of BIT225 with recombinant interferon alpha-2b (rIFNalpha-2b) show synergistic antiviral action against BVDV and the synergy is further enhanced by addition of ribavirin. Synergy was also observed between BIT225 and two nucleoside analogues known to inhibit the HCV RNA-dependent RNA polymerase. BIT225 has successfully completed a phase Ia dose escalating, single dose safety trial in healthy volunteers and a phase Ib/IIa trial to evaluate the safety and pharmacokinetics of repeated dosing for selected doses of BIT225 in HCV-infected persons. A modest, but statistically significant drop in patient viral load was detected over the 7 days of dosing (ref. www.biotron.com.au). Given the critical role of the p7 protein in the HCV life cycle and pathogenicity, our data indicate that molecules like BIT225, representing a new class of antiviral compounds, may be developable for therapeutic use against HCV infection, either as monotherapy, or in combination with other HCV drugs.
Luscombe
Carolyn A
CA
Biotron Limited, Sydney, NSW, Australia.
Huang
Zhuhui
Z
Murray
Michael G
MG
Miller
Michelle
M
Wilkinson
John
J
Ewart
Gary D
GD
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D002986:Clinical Trials as Topic; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D015394:Molecular Structure; D011994:Recombinant Proteins; D012254:Ribavirin / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D000086082:Viroporin Proteins
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins