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Article

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

1
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
2
Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2020, 12(8), 901; https://doi.org/10.3390/v12080901
Received: 16 June 2020 / Revised: 11 August 2020 / Accepted: 14 August 2020 / Published: 17 August 2020
(This article belongs to the Special Issue Hepatitis B Virus: From Diagnostics to Treatments)
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. View Full-Text
Keywords: HBV; inhibitor of apoptosis proteins; IAP; IAP antagonist; Smac-mimetics; TNF; cell death; MDR1 inhibitor; combination therapy HBV; inhibitor of apoptosis proteins; IAP; IAP antagonist; Smac-mimetics; TNF; cell death; MDR1 inhibitor; combination therapy
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MDPI and ACS Style

Morrish, E.; Mackiewicz, L.; Silke, N.; Pellegrini, M.; Silke, J.; Brumatti, G.; Ebert, G. Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo. Viruses 2020, 12, 901. https://doi.org/10.3390/v12080901

AMA Style

Morrish E, Mackiewicz L, Silke N, Pellegrini M, Silke J, Brumatti G, Ebert G. Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo. Viruses. 2020; 12(8):901. https://doi.org/10.3390/v12080901

Chicago/Turabian Style

Morrish, Emma, Liana Mackiewicz, Natasha Silke, Marc Pellegrini, John Silke, Gabriela Brumatti, and Gregor Ebert. 2020. "Combinatorial Treatment of Birinapant and Zosuquidar Enhances Effective Control of HBV Replication In Vivo" Viruses 12, no. 8: 901. https://doi.org/10.3390/v12080901

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