Repurposing existing drugs and discovering new antivirals for hepatitis C

2015

Challenge

Current therapies for the treatment of hepatitis C have improved substantially, but there are still serious limitations and unmet needs for patients, with cost being the most important barrier to effective clinical care.

Advance

IRP researchers, led by T. Jake Liang, M.D., developed a novel cell-based high-throughput assay to screen several small-molecule libraries. Through these efforts they identified a class of antihistamines and several novel compounds with the potential to act as potent hepatitis C virus (HCV) inhibitors in vitro and in vivo. These compounds have since been optimized by medicinal chemistry for preclinical development.

Impact

The discovery of approved antihistamine drugs with anti-HCV properties could facilitate the repurposing of these drugs for the treatment of hepatitis C. In the future it may also be possible to take novel compounds with higher potencies and better pharmacological properties and develop them into clinically-viable HCV drugs.

Publications

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.

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, 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.

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. (2015). Discovery, optimization, and characterization of novel chlorcyclizine derivatives for the treatment of hepatitis C virus infection. J Med Chem. 59(3):841-853.