Evidence for distinct mechanisms of small molecule inhibitors of filovirus entry
| Autor: | Hyun Lee, Adam Schafer, Lijun Rong, Norton P. Peet, Yangfeng Li, Raghad Nowar, Rui Xiong, Erica Ollmann Saphire, Han Cheng, Michael Caffrey, Laura Cooper, Benjamin E. Ramirez, Gregory R. J. Thatcher |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
RNA viruses
Glycobiology Pathology and Laboratory Medicine medicine.disease_cause Biochemistry Binding Analysis 0302 clinical medicine Viral Envelope Proteins Chlorocebus aethiops Medicine and Health Sciences Biology (General) chemistry.chemical_classification 0303 health sciences Organic Compounds Ebolavirus Small molecule Cell biology Chemistry medicine.anatomical_structure Medical Microbiology Filoviruses Viral Pathogens Viruses Physical Sciences Host-Pathogen Interactions Engineering and Technology Marburg Virus Pathogens Cellular Structures and Organelles medicine.symptom Ebola Virus Research Article Biotechnology Viral Entry QH301-705.5 Immunology Drug design Bioengineering Research and Analysis Methods Antiviral Agents Microbiology Small Molecule Libraries 03 medical and health sciences Viral entry Virology Lysosome Genetics medicine Animals Humans Binding site Microbial Pathogens Vero Cells Molecular Biology Chemical Characterization Glycoproteins 030304 developmental biology Virus Glycoproteins Ebola virus Biology and life sciences Hemorrhagic Fever Viruses Organic Chemistry Organisms Chemical Compounds Cell Biology Hemorrhagic Fever Ebola Virus Internalization RC581-607 chemistry Mechanism of action Small Molecules A549 Cells Parasitology Immunologic diseases. Allergy Lysosomes Glycoprotein Viral Transmission and Infection 030217 neurology & neurosurgery |
| Zdroj: | PLoS Pathogens, Vol 17, Iss 2, p e1009312 (2021) PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | Many small molecules have been identified as entry inhibitors of filoviruses. However, a lack of understanding of the mechanism of action for these molecules limits further their development as anti-filoviral agents. Here we provide evidence that toremifene and other small molecule entry inhibitors have at least three distinctive mechanisms of action and lay the groundwork for future development of anti-filoviral agents. The three mechanisms identified here include: (1) direct binding to the internal fusion loop region of Ebola virus glycoprotein (GP); (2) the HR2 domain is likely the main binding site for Marburg virus GP inhibitors and a secondary binding site for some EBOV GP inhibitors; (3) lysosome trapping of GP inhibitors increases drug exposure in the lysosome and further improves the viral inhibition. Importantly, small molecules targeting different domains on GP are synergistic in inhibiting EBOV entry suggesting these two mechanisms of action are distinct. Our findings provide important mechanistic insights into filovirus entry and rational drug design for future antiviral development. Author summary Filoviruses are among the deadliest pathogens known to mankind with case-fatality rates ranging from 25–90%. New outbreaks in central Africa and the identification of novel filoviruses in other regions highlight the urgent need to develop novel therapeutics. Although many novel anti-filovirus compounds have been reported as entry inhibitors, to date, none have made to market. This high rate of failure is in part due to a lack of knowledge of the mechanisms of action. In this report, we provide a molecular basis for the multiple mechanisms of action by which small molecule inhibitors of Ebola virus and Marburg virus block virus entry, which provides new mechanistic insight to guide design for next-generation viral entry inhibitors. |
| Databáze: | OpenAIRE |
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