Evolution of Intermediates during Capsid Assembly of Hepatitis B Virus with Phenylpropenamide-Based Antivirals

被引:10
|
作者
Kondylis, Panagiotis [1 ]
Schlicksup, Christopher J. [2 ]
Katen, Sarah P. [2 ]
Lee, Lye Siang [2 ]
Zlotnick, Adam [2 ]
Jacobson, Stephen C. [1 ]
机构
[1] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA
[2] Indiana Univ, Dept Mol & Cellular Biochem, Bloomington, IN 47405 USA
来源
ACS INFECTIOUS DISEASES | 2019年 / 5卷 / 05期
关键词
resistive-pulse sensing; hepatitis B virus; phenylpropenamides; assembly intermediates; self-assembly; RESISTIVE-PULSE ANALYSIS; DERIVATIVES; REPLICATION; INHIBITION; DEVICES; MODEL; AT-61; TIME;
D O I
10.1021/acsinfecdis.8b00290
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Self-assembly of virus capsids is a potential target for antivirals due to its importance in the virus lifecycle. Here, we investigate the effect of phenylpropenamide derivatives B-21 and AT-130 on the assembly of hepatitis B virus (HBV) core protein. Phenylpropenamides are widely believed to yield assembly of spherical particles resembling native, empty HBV capsids. Because the details of assembly can be overlooked with ensemble measurements, we performed resistive-pulse sensing on nanofluidic devices with four pores in series to characterize the size distributions of the products in real time. With its single particle sensitivity and compatibility with typical assembly buffers, resistive-pulse sensing is well-suited for analyzing virus assembly in vitro. We observed that assembly with B-21 and AT-130 produced a large fraction of partially complete virus particles that may be on-path, off-path, or trapped. For both B-21 and AT-130, capsid assembly was more sensitive to disruption under conditions where the interprotein association energy was low at lower salt concentrations. Dilution of the reaction solutions led to the rearrangement of the incomplete particles and demonstrated that these large intermediates may be on-path, but are labile, and exist in a frustrated dynamic equilibrium. During capsid assembly, phenylpropenamide molecules modestly increase the association energy of dimers, prevent intermediates from dissociating, and lead to kinetic trapping where the formation of too many capsids has been initiated, which results in both empty and incomplete particles.
引用
收藏
页码:769 / 777
页数:17
相关论文
共 50 条
  • [41] Antigenic diversity of the hepatitis B virus capsid
    Harris, Audray
    Belnap, David
    Watts, Norman
    Conway, James
    Cheng, Naiqian
    Stahl, Stephen
    Wingfield, Paul
    Steven, Alasdair
    RETROVIROLOGY, 2005, 2 (Suppl 1)
  • [42] Capsid assembly modulator for chronic hepatitis B infection
    Baker, Holly
    LANCET GASTROENTEROLOGY & HEPATOLOGY, 2023, 8 (04): : 304 - 304
  • [43] A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly
    Xi, Jingyuan
    Gu, Zhiqiang
    Sun, Chunyan
    Chen, Zimin
    Zhang, Ting
    Chen, Ran
    Liu, Tianyu
    Liao, Hao
    Zou, Jun
    Yang, Danli
    Xu, Qiang
    Wang, Jie
    Wei, Guochao
    Cheng, Zhe
    Lu, Fengmin
    Chen, Xiangmei
    ANTIVIRAL RESEARCH, 2023, 218
  • [44] BAY 41-4109 has multiple effects on Hepatitis B virus capsid assembly
    Stray, Stephen J.
    Zlotnick, Adam
    JOURNAL OF MOLECULAR RECOGNITION, 2006, 19 (06) : 542 - 548
  • [45] Dynamics of Hepatitis B Virus Capsid Protein Dimer Regulate Assembly through an Allosteric Network
    Patterson, Angela
    Zhao, Zhongchao
    Waymire, Elizabeth
    Zlotnick, Adam
    Bothner, Brian
    ACS CHEMICAL BIOLOGY, 2020, 15 (08) : 2273 - 2280
  • [46] Small-Molecule Effectors of Hepatitis B Virus Capsid Assembly Give Insight into Virus Life Cycle
    Bourne, Christina
    Lee, Sejin
    Venkataiah, Bollu
    Lee, Angela
    Korba, Brent
    Finn, M. G.
    Zlotnick, Adam
    JOURNAL OF VIROLOGY, 2008, 82 (20) : 10262 - 10270
  • [47] Acetophenone 4-nitrophenylhydrazone inhibits Hepatitis B virus replication by modulating capsid assembly
    Yamasaki, Manabu
    Matsuda, Norie
    Matoba, Kazuaki
    Kondo, Saki
    Kanegae, Yumi
    Saito, Izumu
    Nomoto, Akio
    VIRUS RESEARCH, 2021, 306
  • [48] An automated microfluidic platform for the screening and characterization of novel hepatitis B virus capsid assembly modulators
    Vermes, Tamas
    Kielpinski, Mark
    Henkel, Thomas
    Pericas, Miquel A.
    Alza, Esther
    Corcuera, Angelica
    Buschmann, Helmut
    Goldner, Thomas
    Urban, Andreas
    ANALYTICAL METHODS, 2022, 14 (02) : 135 - 146
  • [49] A New Role for Capsid Assembly Modulators To Target Mature Hepatitis B Virus Capsids and Prevent Virus Infection
    Ko, Chunkyu
    Bester, Romina
    Zhou, Xue
    Xu, Zhiheng
    Blossey, Christoph
    Sacherl, Julia
    Vondran, Florian W. R.
    Gao, Lu
    Protzer, Ulrike
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2020, 64 (01)
  • [50] IDENTIFICATION AND CHARACTERIZATION OF A HEPATITIS C VIRUS CAPSID ASSEMBLY INHIBITOR
    Gentzsch, J.
    Hurt, C. R.
    Lingappa, V. R.
    Pietschmann, T.
    JOURNAL OF HEPATOLOGY, 2011, 54 : S29 - S29