Hepatitis C: Repurposing existing drugs and discovering new antivirals
Treatments for hepatitis C virus (HCV) have improved substantially over the years, but serious limitations and unmet needs still exist for patients, with cost being the biggest barrier to effective clinical care.
IRP researchers led by T. Jake Liang, M.D., developed a novel cell-based high-throughput assay to screen several expansive small-molecule libraries, including a pharmaceutical collection, for activity against HCV. They identified a class of antihistamines and several novel compounds as potent HCV inhibitors in vitro and in vivo. The compounds have since been optimized by medicinal chemistry for preclinical development.
The discovery that approved antihistamine drugs have anti-HCV properties can facilitate repurposing of those compounds for HCV treatment more quickly than developing new drugs for testing and approval. Additionally, it may be possible to bring the novel compounds identified to have higher potencies and better pharmacological properties forward through testing into clinically-viable HCV drugs.
Hu Z, Lan KH, He S, Swaroop M, Hu X, Southall N, Zheng W, Liang TJ. (2014). Novel cell-based hepatitis C virus infection assay for quantitative high throughput screening of anti-hepatitis C virus compounds. Antimicrob Agents Chemother. 58(2):995-1004.
He S, Lin B, Chu V, Hu Z, Hu X, Xiao J, Wang AQ, Schweitzer CJ, Li Q, Imamura M, Hiraga N, Southall N, Ferrer M, Zheng W, Chayama K, Marugan JJ, Liang TJ. (2015). Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection. Science Transl Med. 7(282):282ra49.
Hu Z, Hu X, He S, Yim HJ, Xiao J, Swaroop M, Tanega C, Zhang YQ, Yi G, Kao CC, Marugan J, Ferrer M, Zheng W, Southall N, Liang TJ. (2015). Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay. Antiviral Res. 124:20-29.
He S, Xiao J, Dulcey, AE, Rolt A, Hu Z, Hu X, Wang AQ, Xu X, Southall N, Ferrer M, Zheng W, Liang TJ, Marugan JJ. (2016). Discovery, optimization, and characterization of novel chlorcyclizine derivatives for the treatment of hepatitis C virus infection. J Med Chem. 59(3):841-853.