The development of therapeutics that increase cure rates in the treatment of hepatitis B will likely require multiple agents that target different mechanisms within the HBV viral life cycle. One clinically validated approach that inhibits viral replication in a manner that is distinct from existing nucleos(t)ide-based polymerase inhibitors involves modulation of the HBV capsid assembly process through binding with HBV core protein (Cp) and preventing the essential step of pregenomic RNA (pgRNA) encapsidation. Furthermore, such agents can inhibit the capsid uncoating process, affecting the formation of covalently closed circular DNA (cccDNA) and the replenishment of the nuclear cccDNA pool. As such, there is a great deal of interest in identifying capsid inhibitors with increased potency against both mechanisms. The availability of X-ray crystallographic data for capsid inhibitors in complex with a Y132A mutant of the assembly domain of HBV Cp has identified key electrostatic and steric interactions accessible within the Cp binding site and has allowed for the rational design of new chemotypes. Through definition of a minimal pharmacophore, a novel series of isoquinolinone-based capsid inhibitors was identified. Optimization of potency and further structural biology analysis revealed that lead molecules possess a unique binding mode at the Cp dimer:dimer interface, exploiting an additional electrostatic interaction with an accessible tyrosine residue. Key analogs demonstrated low dose q.d. efficacy in an in vivo mouse model of HBV infection and maintained in vitro antiviral activity against clinically relevant variants of HBV Cp. Based on these results, isoquinolinone derivative AB-836 was selected for progression into clinical development. Initial data from a phase 1b proof of concept study in chronic hepatitis B patients receiving a once daily 100 mg dose of AB-836 for 28 days (N=4) showed robust antiviral activity with a mean reduction of 3.1 log10 in HBV DNA from baseline. The excellent preclinical profile and emerging clinical data support further development of AB-836.

Rational design of a novel series of HBV capsid inhibitors leading to the identification of clinical candidate AB-836

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ACS Fall 2022

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