乙肝病毒衣壳必须绑定到HAP口袋小分子配体不同的结构响应

StephenW

J Virol. 2016 Feb 3. pii: JVI.03058-15. [Epub ahead of print]
Hepatitis B virus capsids have diverse structural responses to small molecule ligands bound to the HAP pocket.Venkatakrishnan B1, Katen SP2, Francis S3, Chirapu S4, Finn MG4, Zlotnick A5.
Author information

• 1Molecular and Cellular Biochemistry Department, Indiana University, 212 S Hawthorne Drive Bloomington Indiana 47405 USA.
• 2Assembly Biosciences, 212 S Hawthorne Drive Bloomington Indiana 47405 USA and 409 Illinois Street San Francisco California 99156 USA.
• 3Molecular and Cellular Biochemistry Department, Indiana University, 212 S Hawthorne Drive Bloomington Indiana 47405 USA Assembly Biosciences, 212 S Hawthorne Drive Bloomington Indiana 47405 USA and 409 Illinois Street San Francisco California 99156 USA.
• 4Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road La Jolla California 92037 Georgia Institute of Technology, School of Chemistry and Biochemistry 901 Atlantic Drive Atlanta Georgia 30322 USA.
• 5Molecular and Cellular Biochemistry Department, Indiana University, 212 S Hawthorne Drive Bloomington Indiana 47405 USA [email protected].
  

AbstractThough the Hepatitis B virus (HBV) core protein is an important participant in many aspects of the viral life cycle, its best-characterized activity is self-assembly into 240-monomer capsids. Small-molecules that target core protein (Core protein Allosteric Modulators, CpAMs) represent a promising antiviral strategy. To better understand the structural basis of CpAM mechanism, we determined the crystal structure of the HBV capsid in complex with HAP18. HAP18 accelerates assembly, increases protein-protein association by more than 100-fold, and induces assembly of non-icosahedral macro-structures. In a preformed capsid, HAP18 is found at quasi-equivalent subunit-subunit interfaces. In detailed comparison to the two other extant CpAM structures, we find that the HAP18-capsid structure presents a paradox. Where the two other structures expanded the capsid diameter by up to 10Å, HAP18 caused only minor changes in quaternary structure and actually decreased capsid diameter by ∼3Å. These results indicate that CpAMs do not have a single allosteric effect on capsid structure. We suggest that HBV capsids present an ensemble of states that can be trapped by CpAMs, indicating a more complex basis for antiviral drug design.
IMPORTANCE: Hepatitis B Virus core protein has multiple roles in the viral lifecycle - assembly, compartment for reverse transcription, intracellular trafficking, nuclear functions - making it an attractive antiviral target. Core protein allosteric modulators (CpAMs), are an experimental class of antiviral that bind core protein. The most accessible CpAM activity is that they accelerate core protein assembly and strengthen interactions between subunits. In this study, we observe that the CpAM-binding pocket has multiple conformations. We compare structures of capsids co45 crystallized with different CpAMs and find that they also affect quaternary structure in different ways. These results suggest that the capsid breathes and is trapped in different states by the drug and crystallization. Understanding that the capsid is a moving target will aid drug design and improve our understanding of HBV interaction with its environment.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.

StephenW

病毒学杂志。 2016年3月PII：JVI.03058-15。 [打印EPUB提前]
乙肝病毒衣壳必须绑定到HAP口袋小分子配体不同的结构响应。
Venkatakrishnan B1，卡滕SP2，弗朗西斯S3，S4 Chirapu，芬兰人MG4，Zlotnick A5。
作者信息1Molecular与细胞生物化学系，美国印第安纳大学，212小号霍桑Drive布卢明顿印第安纳州47405 USA。 2Assembly生物科学，212小号霍桑Drive布卢明顿47405印第安纳州和美国伊利诺伊州409街旧金山加利福尼亚州99156 USA。 3分子与细胞生物化学系，美国印第安纳大学，212小号霍桑Drive布卢明顿印第安纳州47405美国生物科学大会，212小号霍桑Drive布卢明顿47405印第安纳州和美国伊利诺伊州409街旧金山加利福尼亚州99156 USA。化学4Department和斯卡格斯学院化学生物学，斯克里普斯研究所，10550北多利松路拉霍亚加州92037佐治亚理工学院，中学化学与生物化学901大西洋驱动乔治亚州亚特兰大的美国30322。 5Molecular与细胞生物化学系，美国印第安纳大学，212小号霍桑Drive布卢明顿印第安纳州47405美国[email protected]。
抽象
虽然乙型肝炎病毒（HBV）核心蛋白是在病毒生命周期的许多方面的重要参与者，其最佳表征的活性是自组装成240单体衣壳。针对核心蛋白（核心蛋白变构调节剂，CpAMs）小分子代表一个有前途的抗病毒策略。为了更好地了解的CPAM机构的结构的基础上，我们确定了在复杂的HAP18乙肝衣壳的晶体结构。 HAP18加速组装，超过100倍增加蛋白质的关联，并诱导非二十面体宏观结构的组装。在一预成形壳体，HAP18在准等效亚基 - 亚基界面找到。在详细比较其他两个现存的CPAM结构，我们发现，HAP18衣壳的结构提出了一个悖论。其中两个其他结构高达10A的扩张衣壳直径，HAP18造成四级结构只有轻微的变化，实际上是由~3Å下降衣壳直径。这些结果表明，CpAMs不会对衣壳结构的单变构效应。我们认为，乙肝病毒衣壳目前可以由CpAMs被困状态，这表明抗病毒的药物设计更复杂的基础合奏。
重要性：
乙型肝炎病毒核心蛋白在病毒生命周期的多重角色 - 组装，车厢进行反转录，细胞内运输，核功能 - 使之成为一个有吸引力的抗病毒的目标。核心蛋白变构调节剂（CpAMs），是一个实验班的抗病毒药物结合核心蛋白。最方便的CPAM的活动是他们加速核心蛋白装配和加强亚基之间的相互作用。在这项研究中，我们观察到CPAM结合袋具有多个构象。我们比较不同CpAMs结晶衣壳co45的结构，发现他们也以不同的方式影响四级结构。这些结果表明，衣壳呼吸，由药物和结晶被困在不同的状态。了解该衣壳是一个移动的目标将有助于药物设计和改善我们与环境的互动乙肝的认识。
版权所有©2016年，美国微生物学会。版权所有。

MP4

Assembly Biosciences, however, is focused on targeting HBVs core proteins in novel ways with the specific goal of helping patients attain a clinical cure.

Assembly has discovered multiple novel series of HBV core protein allosteric modulators (CpAMs) representing what we believe to be a best-in-class pipeline. The HBV core protein is a highly conserved viral protein that has no human homologue and is involved in multiple steps of the HBV lifecycle. Modulation of this target with Assemblys CpAMs has demonstrated preclinical proof of principle. CpAMs can selectively reduce the production of key viral antigens as well as viral load via its novel mechanism in multiple cell models.

Work to select a first generation lead molecule is currently underway. The CpAM platform offers opportunities for a multi-generation pipeline, and we plan to move our second generation CpAMs into development immediately behind the first generation program.

HBV is a debilitating disease that afflicts hundreds of millions of people worldwide, and many of those currently infected cannot be cured. Assemblys CpAM pipeline with curative potential addresses a major global unmet medical need and represents a multi-billion dollar market opportunity.
http://www.assemblybio.com/ab/?page_id=2751

StephenW

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是的，亚当 Zlotnick博士，作者之一，也是Assembly的创始人, 他的研究是非常高的水平.

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好文

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