High-resolution Crystal Structure of a Hepatitis B Virus Replication Inhibitor Bound to the Viral Core Protein

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Nov 25

PMID 26598693

Citations 60

Authors

Klaus Klumpp

Angela M Lam

Christine Lukacs

Robert Vogel

Suping Ren

Christine Espiritu

Ruth Baydo

Kateri Atkins

Jan Abendroth

Guochun Liao

Andrey Efimov

George Hartman

Osvaldo A Flores

Affiliations

Soon will be listed here.

Abstract

The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010-001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a Tm increase of more than 10 °C. NVR-010-001-E2 binds at the dimer-dimer interface of the core proteins, forms a new interaction surface promoting protein-protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010-001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein-protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties.

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References

Zhang J, Yao X, Wang Y, Liu F, Ma Z, Weng X . High replicative full-length lamivudine-resistant hepatitis B virus isolated during acute exacerbations. J Med Virol. 2005; 77(2):203-8. DOI: 10.1002/jmv.20453. View

Weber O, Schlemmer K, Hartmann E, Hagelschuer I, Paessens A, GRAEF E . Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antiviral Res. 2002; 54(2):69-78. DOI: 10.1016/s0166-3542(01)00216-9. View

Dryden K, Wieland S, Whitten-Bauer C, Gerin J, Chisari F, Yeager M . Native hepatitis B virions and capsids visualized by electron cryomicroscopy. Mol Cell. 2006; 22(6):843-850. DOI: 10.1016/j.molcel.2006.04.025. View

Bourne C, Finn M, Zlotnick A . Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1. J Virol. 2006; 80(22):11055-61. PMC: 1642186. DOI: 10.1128/JVI.00933-06. View

Zlotnick A, Lee A, Bourne C, Johnson J, Domanico P, Stray S . In vitro screening for molecules that affect virus capsid assembly (and other protein association reactions). Nat Protoc. 2007; 2(3):490-8. PMC: 2099249. DOI: 10.1038/nprot.2007.60. View

Packianathan C, Katen S, Dann 3rd C, Zlotnick A . Conformational changes in the hepatitis B virus core protein are consistent with a role for allostery in virus assembly. J Virol. 2009; 84(3):1607-15. PMC: 2812345. DOI: 10.1128/JVI.02033-09. View

Bourne C, Katen S, Fulz M, Packianathan C, Zlotnick A . A mutant hepatitis B virus core protein mimics inhibitors of icosahedral capsid self-assembly. Biochemistry. 2009; 48(8):1736-42. PMC: 2880625. DOI: 10.1021/bi801814y. View

Brezillon N, Brunelle M, Massinet H, Giang E, Lamant C, DaSilva L . Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice. PLoS One. 2011; 6(12):e25096. PMC: 3230577. DOI: 10.1371/journal.pone.0025096. View

Wang X, Wei Z, Wu G, Wang J, Zhang Y, Li J . In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations. Antivir Ther. 2012; 17(5):793-803. DOI: 10.3851/IMP2152. View

10.

Campagna M, Liu F, Mao R, Mills C, Cai D, Guo F . Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids. J Virol. 2013; 87(12):6931-42. PMC: 3676120. DOI: 10.1128/JVI.00582-13. View

11.

Alexander C, Jurgens M, Shepherd D, Freund S, Ashcroft A, Ferguson N . Thermodynamic origins of protein folding, allostery, and capsid formation in the human hepatitis B virus core protein. Proc Natl Acad Sci U S A. 2013; 110(30):E2782-91. PMC: 3725087. DOI: 10.1073/pnas.1308846110. View

12.

Katen S, Tan Z, Chirapu S, Finn M, Zlotnick A . Assembly-directed antivirals differentially bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure. Structure. 2013; 21(8):1406-16. PMC: 3756818. DOI: 10.1016/j.str.2013.06.013. View

13.

Wu G, Liu B, Zhang Y, Li J, Arzumanyan A, Clayton M . Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly. Antimicrob Agents Chemother. 2013; 57(11):5344-54. PMC: 3811253. DOI: 10.1128/AAC.01091-13. View

14.

Cowie B, Carville K, MacLachlan J . Mortality due to viral hepatitis in the Global Burden of Disease Study 2010: new evidence of an urgent global public health priority demanding action. Antivir Ther. 2013; 18(8):953-4. DOI: 10.3851/IMP2654. View

15.

Klumpp K, Crepin T . Capsid proteins of enveloped viruses as antiviral drug targets. Curr Opin Virol. 2014; 5:63-71. DOI: 10.1016/j.coviro.2014.02.002. View

16.

Cho M, Jeong H, Kim Y, Kim J, Jung G . 2-amino-N-(2,6-dichloropyridin-3-yl)acetamide derivatives as a novel class of HBV capsid assembly inhibitor. J Viral Hepat. 2013; 21(12):843-52. DOI: 10.1111/jvh.12214. View

17.

Zlotnick A, Ceres P, Singh S, Johnson J . A small molecule inhibits and misdirects assembly of hepatitis B virus capsids. J Virol. 2002; 76(10):4848-54. PMC: 136179. DOI: 10.1128/jvi.76.10.4848-4854.2002. View

18.

Bourne C, Lee S, Venkataiah B, Lee A, Korba B, Finn M . Small-molecule effectors of hepatitis B virus capsid assembly give insight into virus life cycle. J Virol. 2008; 82(20):10262-70. PMC: 2566253. DOI: 10.1128/JVI.01360-08. View

19.

Deres K, Schroder C, Paessens A, Goldmann S, Hacker H, Weber O . Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science. 2003; 299(5608):893-6. DOI: 10.1126/science.1077215. View

20.

Wynne S, Crowther R, Leslie A . The crystal structure of the human hepatitis B virus capsid. Mol Cell. 1999; 3(6):771-80. DOI: 10.1016/s1097-2765(01)80009-5. View