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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Discovery of Novel Hepatitis B Virus Nucleocapsid Assembly Inhibitors
ACS infectious diseases, v 5(5), pp 759-768
10 May 2019
PMCID: PMC6510629
PMID: 30525438
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Hepatitis B virus (HBV) core protein is a small protein with 183 amino acid residues and assembles the pregenomic (pg) RNA and viral DNA polymerase to form nucleocapsids. During the last decades, several groups have reported HBV core protein allosteric modulators (CpAMs) with distinct chemical structures. CpAMs bind to the hydrophobic HAP pocket located at the dimer-dimer interface and induce allosteric conformational changes in the core protein subunits. While Type I CpAMs, heteroaryldihydropyrimidine (HAP) derivatives, misdirect core protein dimers to assemble noncapsid polymers, Type II CpAMs, represented by sulfamoylbenzamides, phenylpropenamides, and several other chemotypes, induce the assembly of empty capsids with global structural alterations and faster mobility in native agarose gel electrophoresis. Through high throughput screening of an Asinex small molecule library containing 19 920 compounds, we identified 8 structurally distinct CpAMs. While 7 of those compounds are typical Type II CpAMs, a novel benzamide derivative, designated as BA-53038B, induced the formation of morphologically "normal" empty capsids with slow electrophoresis mobility. Drug resistant profile analyses indicated that BA-53038B most likely bound to the HAP pocket but obviously modulated HBV capsid assembly in a distinct manner. BA-53038B and other CpAMs reported herein provide novel structure scaffolds for the development of core protein-targeted antiviral agents for the treatment of chronic hepatitis B.
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Details
- Title
- Discovery of Novel Hepatitis B Virus Nucleocapsid Assembly Inhibitors
- Creators
- Xuexiang Zhang - Baruch S. Blumberg InstituteJunjun Cheng - Baruch S. Blumberg InstituteJulia Ma - Baruch S. Blumberg InstituteZhanying Hu - Baruch S. Blumberg InstituteShuo Wu - Baruch S. Blumberg InstituteNicky Hwang - Baruch S. Blumberg InstituteJohn Kulp - Baruch S. Blumberg InstituteYanming Du - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg InstituteJinhong Chang - Baruch S. Blumberg Institute
- Publication Details
- ACS infectious diseases, v 5(5), pp 759-768
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R01 AI134732 / NIAID NIH HHS R01 AI113267 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000468015100011
- Scopus ID
- 2-s2.0-85059369875
- Other Identifier
- 991020547324004721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Medicinal
- Infectious Diseases