Related Experiment Video
Updated: Jul 22, 2026
Development of a Hepatitis B Virus Reporter System to Monitor the Early Stages of the Replication Cycle
Published on: February 1, 2017
Discovery of Hepatitis B Virus Surface Antigen Suppressor GS-8873
Darryl Kato1, Regina Wai-Yan Choy1, Eda Canales1
1Gilead Sciences, Foster City, California 94404, United States.
Insights
Researchers developed GS-8873, a new drug targeting chronic hepatitis B (CHB) by suppressing HBsAg. This orally available compound aims to restore immune function for a potential functional cure of CHB infection.
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Chronic hepatitis B (CHB) affects millions globally, causing significant mortality.
- High HBsAg levels in CHB contribute to T-cell exhaustion and impaired immunity.
- HBsAg suppression is a key strategy for achieving a functional cure for CHB.
Purpose of the Study:
- To discover a potent, orally bioavailable, and safe PAPD5/7 inhibitor.
- To develop a novel therapeutic agent for CHB functional cure regimens.
- To identify a compound capable of deep HBsAg suppression.
Main Methods:
- Investigated dihydropyridoisoquinolizinone (DHQ) inhibitors of PAPD5/7.
- Developed a dihydropyridophthalazinone (DPP) core with enhanced pharmacokinetics.
- Employed conformational restriction and core substitution optimization.
Main Results:
- Identified GS-8873, a novel DPP-based PAPD5/7 inhibitor.
- GS-8873 demonstrated improved pharmacokinetic properties over previous inhibitors.
- GS-8873 is projected to achieve deep HBsAg suppression with once-daily dosing.
Conclusions:
- GS-8873 represents a promising candidate for CHB functional cure.
- The DPP core offers advantages for developing effective CHB therapies.
- Further development of GS-8873 could significantly impact CHB management.
Abstract:
Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.
