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ACS Infect Dis. 2018 Dec 10. doi: 10.1021/acsinfecdis.8b00269. [Epub ahead of print]
Discovery of novel hepatitis B virus nucleocapsid assembly inhibitors.
Zhang X, Cheng J, Ma J, Hu Z, Wu S, Hwang N, Kulp J, Du Y, Guo JT, Chang J.
Abstract
Hepatitis B virus (HBV) core protein is a small protein with 183 amino acid residues and assembles the pre-genomic (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 non-capsid 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.
PMID:
30525438
DOI:
10.1021/acsinfecdis.8b00269 |
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