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靶向乙肝病毒衣壳疏水口袋的配体的药物调节作用

Pharmacomodulation of a ligand targeting the HBV capsid hydrophobic pocket.

作者信息

Briday Mathilde, Hallé François, Lecoq Lauriane, Radix Sylvie, Martin Juliette, Montserret Roland, Dujardin Marie, Fogeron Marie-Laure, Nassal Michael, Meier Beat H, Lomberget Thierry, Böckmann Anja

机构信息

Molecular Microbiology and Structural Biochemistry (MMSB) UMR 5086 CNRS/Université de Lyon, Labex Ecofect 7 Passage du Vercors 69367 Lyon France

Université de Lyon, Université Lyon 1, CNRS UMR 5246 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Faculté de Pharmacie-ISPB 8 Avenue Rockefeller FR-69373 Lyon Cedex 08 France

出版信息

Chem Sci. 2022 Jul 7;13(30):8840-8847. doi: 10.1039/d2sc02420a. eCollection 2022 Aug 4.

DOI:10.1039/d2sc02420a
PMID:36042894
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9358932/
Abstract

Hepatitis B virus (HBV) is a small enveloped retrotranscribing DNA virus and an important human pathogen. Its capsid-forming core protein (Cp) features a hydrophobic pocket proposed to be central notably in capsid envelopment. Indeed, mutations in and around this pocket can profoundly modulate, and even abolish, secretion of enveloped virions. We have recently shown that Triton X-100, a detergent used during Cp purification, binds to the hydrophobic pocket with micromolar affinity. We here performed pharmacomodulation of pocket binders through systematic modifications of the three distinct chemical moieties composing the Triton X-100 molecule. Using NMR and ITC, we found that the flat aromatic moiety is essential for binding, while the number of atoms of the aliphatic chain modulates binding affinity. The hydrophilic tail, in contrast, is highly tolerant to changes in both length and type. Our data provide essential information for designing a new class of HBV antivirals targeting capsid-envelope interactions.

摘要

乙型肝炎病毒（HBV）是一种小型包膜逆转录DNA病毒，也是一种重要的人类病原体。其形成衣壳的核心蛋白（Cp）具有一个疏水口袋，该口袋被认为在衣壳包膜过程中起着关键作用。实际上，这个口袋及其周围的突变能够深刻地调节甚至消除包膜病毒粒子的分泌。我们最近发现，在Cp纯化过程中使用的去污剂Triton X-100以微摩尔亲和力与疏水口袋结合。我们在此通过对构成Triton X-100分子的三个不同化学部分进行系统修饰，对口袋结合剂进行了药物调节。利用核磁共振（NMR）和等温滴定量热法（ITC），我们发现扁平的芳香部分对于结合至关重要，而脂肪链的原子数调节结合亲和力。相比之下，亲水尾部对长度和类型的变化具有高度耐受性。我们的数据为设计一类针对衣壳-包膜相互作用的新型HBV抗病毒药物提供了重要信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/ce108f50ea97/d2sc02420a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/e2f4c136b427/d2sc02420a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/ec717baa7075/d2sc02420a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/01739bae97d7/d2sc02420a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/26debf8bbeaf/d2sc02420a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/71666de41def/d2sc02420a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/7cc7569e3957/d2sc02420a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/ce108f50ea97/d2sc02420a-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/e2f4c136b427/d2sc02420a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/ec717baa7075/d2sc02420a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/01739bae97d7/d2sc02420a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/26debf8bbeaf/d2sc02420a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/71666de41def/d2sc02420a-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/7cc7569e3957/d2sc02420a-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8743/9358932/ce108f50ea97/d2sc02420a-f7.jpg

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Hepatology. 2022 Jul;76(1):233-250. doi: 10.1002/hep.32314. Epub 2022 Feb 16.
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Binding of a Pocket Factor to Hepatitis B Virus Capsids Changes the Rotamer Conformation of Phenylalanine 97.口袋因子与乙型肝炎病毒衣壳的结合改变了苯丙氨酸 97 的构象。
Viruses. 2021 Oct 20;13(11):2115. doi: 10.3390/v13112115.
3
The Hepatitis B Virus Nucleocapsid-Dynamic Compartment for Infectious Virus Production and New Antiviral Target.乙肝病毒核衣壳——传染性病毒产生的动态区室及新的抗病毒靶点
Biomedicines. 2021 Oct 29;9(11):1577. doi: 10.3390/biomedicines9111577.
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Prospects for the Global Elimination of Hepatitis B.全球消除乙型肝炎的前景。
Annu Rev Virol. 2021 Sep 29;8(1):437-458. doi: 10.1146/annurev-virology-091919-062728.
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Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype.乙型肝炎核心蛋白刺突的构象可塑性促进肽结合，且与分泌表型无关。
Microorganisms. 2021 Apr 29;9(5):956. doi: 10.3390/microorganisms9050956.
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Synthesis of "Nereid," a new phenol-free detergent to replace Triton X-100 in virus inactivation.“Nereid”的合成，一种新型不含酚的清洁剂，用于替代病毒灭活中的 Triton X-100。
J Med Virol. 2021 Jun;93(6):3880-3889. doi: 10.1002/jmv.26708. Epub 2020 Dec 17.
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