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2 results on '"Phlebovirus drug effects"'

1. Host specific sphingomyelin is critical for replication of diverse RNA viruses.

Author

Han S, Ye X, Yang J, Peng X, Jiang X, Li J, Zheng X, Zhang X, Zhang Y, Zhang L, Wang W, Li J, Xin W, Zhang X, Xiao G, Peng K, Zhang L, Du X, Zhou L, Liu W, and Li H

Subjects
Animals, Mice, Humans, Mice, Inbred C57BL, Phlebovirus physiology, Phlebovirus drug effects, Phlebovirus metabolism, RNA Viruses drug effects, RNA Viruses physiology, Membrane Proteins metabolism, Membrane Proteins antagonists & inhibitors, Membrane Proteins genetics, Antiviral Agents pharmacology, Antiviral Agents chemistry, Chlorocebus aethiops, Female, Nerve Tissue Proteins, Virus Replication drug effects, Sphingomyelins metabolism, Sphingomyelins chemistry, Transferases (Other Substituted Phosphate Groups) metabolism, Transferases (Other Substituted Phosphate Groups) antagonists & inhibitors, Transferases (Other Substituted Phosphate Groups) genetics, SARS-CoV-2 drug effects, SARS-CoV-2 metabolism
Abstract

Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). SGMS1 knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in SGMS1-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Published
2024
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2. The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target.

Author

Wang W, Shin WJ, Zhang B, Choi Y, Yoo JS, Zimmerman MI, Frederick TE, Bowman GR, Gross ML, Leung DW, Jung JU, and Amarasinghe GK

Subjects
Animals, Antiviral Agents chemistry, Cations, Divalent pharmacology, Cell Line, Conserved Sequence, Crystallography, X-Ray, Dibenzothiepins chemistry, Dibenzothiepins pharmacology, Endonucleases antagonists & inhibitors, Endonucleases metabolism, Humans, Models, Molecular, Morpholines chemistry, Morpholines pharmacology, Protein Domains, Protein Structure, Secondary, Pyridones chemistry, Pyridones pharmacology, Triazines chemistry, Triazines pharmacology, Antiviral Agents pharmacology, Endonucleases chemistry, Phlebovirus drug effects, Phlebovirus enzymology
Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%-30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While the overall structure is similar to those of other cap-snatching sNSV endonucleases, differences near the C terminus of the SFTSV endonuclease suggest divergence in regulation. Influenza virus endonuclease inhibitors, including the US Food and Drug Administration (FDA) approved Baloxavir (BXA), inhibit the endonuclease activity in in vitro enzymatic assays and in cell-based studies. BXA displays potent activity with a half maximal inhibitory concentration (IC 50 ) of ∼100 nM in enzyme inhibition and an EC 50 value of ∼250 nM against SFTSV and HRTV in plaque assays. Together, our data support sNSV endonucleases as an antiviral target., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
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