Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo

Viruses. 2020 Aug 17;12(8):901. doi: 10.3390/v12080901.

Abstract

Chronic hepatitis B virus (HBV) infection remains a global health threat and affects hundreds of millions worldwide. Small molecule compounds that mimic natural antagonists of inhibitor of apoptosis (IAP) proteins, known as Smac-mimetics (second mitochondria-derived activator of caspases-mimetics), can promote the death of HBV-replicating liver cells and promote clearance of infection in preclinical models of HBV infection. The Smac-mimetic birinapant is a substrate of the multidrug resistance protein 1 (MDR1) efflux pump, and therefore inhibitors of MDR1 increase intracellular concentration of birinapant in MDR1 expressing cells. Liver cells are known to express MDR1 and other drug pump proteins. In this study, we investigated whether combining the clinical drugs, birinapant and the MDR1 inhibitor zosuquidar, increases the efficacy of birinapant in killing HBV expressing liver cells. We showed that this combination treatment is well tolerated and, compared to birinapant single agent, was more efficient at inducing death of HBV-positive liver cells and improving HBV-DNA and HBV surface antigen (HBsAg) control kinetics in an immunocompetent mouse model of HBV infection. Thus, this study identifies a novel and safe combinatorial treatment strategy to potentiate substantial reduction of HBV replication using an IAP antagonist.

Keywords: HBV; IAP; IAP antagonist; MDR1 inhibitor; Smac-mimetics; TNF; cell death; combination therapy; inhibitor of apoptosis proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antiviral Agents / therapeutic use*
  • Dibenzocycloheptenes / therapeutic use*
  • Dipeptides / therapeutic use*
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Hep G2 Cells
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / physiology
  • Hepatitis B, Chronic / drug therapy*
  • Humans
  • Indoles / therapeutic use*
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Liver / cytology
  • Liver / drug effects
  • Liver / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Quinolines / therapeutic use*
  • Virus Replication / drug effects*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antiviral Agents
  • Dibenzocycloheptenes
  • Dipeptides
  • Indoles
  • Inhibitor of Apoptosis Proteins
  • Quinolines
  • birinapant
  • zosuquidar trihydrochloride