The HBV core protein serves multiple essential functions in the viral life cycle that enable chronic HBV infection to persist, and as such, represents a promising drug target. Modulation of the HBV capsid assembly has shown efficacy in early clinical trials through use of small molecule capsid assembly modulators (CAMs). Herein is described the evolution and SAR of a novel pyrazolo piperidine lead series into advanced oxadiazepinone HBV CAMs.
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http://dx.doi.org/10.1016/j.bmcl.2021.128353 | DOI Listing |
J Phys Chem B
January 2025
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, United States.
In many simple viruses and virus-like particles, the protein capsid self-assembles around a nucleic-acid genome. Although the assembly process has been studied in detail, relatively little is known about how the capsid disassembles, a potentially important step for infection (in viruses) or cargo delivery (in virus-like particles). We investigate capsid disassembly using a coarse-grained molecular dynamics model of a = 1 dodecahedral capsid and an RNA-like polymer.
View Article and Find Full Text PDFInt J Biol Macromol
January 2025
State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China. Electronic address:
The prompt and efficient identification of targeted inhibitors against unscrupulous pathogenic viruses holds promise for preventing epidemic disease outbreaks. Herein, a comprehensive multichannel screening method (multiple docking cross-validation, molecular dynamics simulation, and density functional theory calculation) integrated with bioactivity identification is rationally established using sugar-based natural ligand libraries to target tobacco mosaic virus (TMV) capsid proteins. Encouragingly, compounds A0 (K = 0.
View Article and Find Full Text PDFMol Divers
January 2025
Environment and Plant Protection Institute, Chinese Academy of Tropical Agricultural Science, Haikou, 571101, China.
In this paper, a series of oxadiazole/thidiazole containing coumarin derivative derivatives were designed, synthesized and characterized using NMR and HRMS. The evaluation of antiviral activity revealed that some of the synthesized compounds exhibited good in vivo antiviral efficacy against tobacco mosaic virus (TMV). Notably, compounds H6 and Y5 demonstrated exceptional therapeutic and protective effects against TMV, with EC values of 180.
View Article and Find Full Text PDFPost-translational modifications play crucial roles in viral infections, yet many potential modifications remain unexplored in orthoflavivirus biology. Here we demonstrate that the UFMylation system, a post-translational modification system that catalyzes the transfer of UFM1 onto proteins, promotes infection by multiple orthoflaviviruses including dengue virus, Zika virus, West Nile virus, and yellow fever virus. We found that depletion of the UFMylation E3 ligase complex proteins UFL1 and UFBP1, as well as other UFMylation machinery components (UBA5, UFC1, and UFM1), significantly reduces infectious virion production for orthoflaviviruses but not the hepacivirus, hepatitis C.
View Article and Find Full Text PDFJ Membr Biol
January 2025
Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, 700073, India.
Dengue virus, an arbovirus from the genus Flavivirus in the family Flaviviridae, forms a nucleocapsid structure through interactions between its genome and multiple copies of the capsid protein. Experimental studies have confirmed the interaction between the viral capsid protein and lipid droplets, indicating a protein-lipid interaction. Cryo-EM studies show that in immature viruses, the nucleocapsid is located close to the viral membrane.
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