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.
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页码:769 / 777
页数:17
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