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1.
Front Microbiol ; 14: 1269869, 2023.
Article in English | MEDLINE | ID: mdl-38075878

ABSTRACT

Scytovirin (SVN) is a lectin from cyanobacteria which has a strong inhibitory activity against Ebola virus infection. We engineered scytovirin as the inhibitor for surface display of lactic acid bacteria to block Ebola virus infection. Two different bacterial strains (Lactobacillus casei and Lactococcus lactis) were successfully engineered for scytovirin expression on the bacterial surface. These bacteria were found to be effective at neutralizing pseudotyped Ebolavirus in a cell-based assay. This approach can be utilized for prophylactic prevention, as well as for treatment. Since lactic acid bacteria can colonize the human body, a long-term efficacy could be achieved. Furthermore, this approach is also simple and cost-effective and can be easily applied in the regions of Ebola outbreaks in the developing countries.

2.
Antiviral Res ; 206: 105399, 2022 10.
Article in English | MEDLINE | ID: mdl-36007601

ABSTRACT

Filoviruses enter cells through macropinocytosis and trafficking into the endosomes in which they bind to the receptor Niemann-Pick C1 protein (NPC1) for membrane fusion and entry into the cytoplasm. The endosomal receptor-binding is critical step for filovirus entry. Designing inhibitors to block receptor binding will prevent viral entry. Using available binding structural information from the co-crystal structures of the viral GP with the receptor NPC1 or with monoclonal antibodies, we have conducted structure-based design of peptide inhibitors to target the receptor binding site (RBS). The designed peptides were tested for their inhibition activity against pseudo-typed or replication-competent viruses in a cell-based assay. The results indicate that these peptides exhibited strong activities against both Ebola and Marburg virus infection. It is expected that these peptides can be further developed for therapeutic use to treat filovirus infection and combat the outbreaks.


Subject(s)
Filoviridae , Receptors, Virus , Viral Fusion Protein Inhibitors , Binding Sites , Carrier Proteins/metabolism , Cell Line , Ebolavirus/physiology , Endosomes/metabolism , Filoviridae/chemistry , Filoviridae/drug effects , Hemorrhagic Fever, Ebola , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Ligands , Membrane Glycoproteins/metabolism , Niemann-Pick C1 Protein/metabolism , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Viral Fusion Protein Inhibitors/chemistry , Viral Fusion Protein Inhibitors/pharmacology , Virus Internalization/drug effects
3.
Antiviral Res ; 189: 105059, 2021 05.
Article in English | MEDLINE | ID: mdl-33705865

ABSTRACT

Filoviruses, mainly consisting of Ebola viruses (EBOV) and Marburg viruses (MARV), are enveloped negative-strand RNA viruses which can infect humans to cause severe hemorrhagic fevers and outbreaks with high mortality rates. The filovirus infection is mediated by the interaction of viral envelope glycoprotein (GP) and the human endosomal receptor Niemann-Pick C1 (NPC1). Blocking this interaction will prevent the infection. Therefore, we utilized an In silico screening approach to conduct virtual compound screening against the NPC1 receptor-binding site (RBS). Twenty-six top-hit compounds were purchased and evaluated by in vitro cell based inhibition assays against pseudotyped or replication-competent filoviruses. Two classes (A and U) of compounds were identified to have potent inhibitory activity against both Ebola and Marburg viruses. The IC50 values are in the lower level of micromolar concentrations. One compound (compd-A) was found to have a sub-micromolar IC50 value (0.86 µM) against pseudotyped Marburg virus. The cytotoxicity assay (MTT) indicates that compd-A has a moderate cytotoxicity level but the compd-U has much less toxicity and the CC50 value was about 100 µM. Structure-activity relationship (SAR) study has found some analogs of compd-A and -U have reduced the toxicity and enhanced the inhibitory activity. In conclusion, this work has identified several qualified lead-compounds for further drug development against filovirus infection.


Subject(s)
Antiviral Agents/pharmacology , Ebolavirus/drug effects , Filoviridae Infections/virology , Marburgvirus/drug effects , Niemann-Pick C1 Protein/metabolism , Viral Envelope Proteins/metabolism , Virus Internalization/drug effects , Antiviral Agents/chemistry , Binding Sites , Cell Survival , Drug Discovery , Ebolavirus/physiology , Filoviridae Infections/drug therapy , HeLa Cells , Host Microbial Interactions/drug effects , Humans , Inhibitory Concentration 50 , Marburgvirus/physiology , Molecular Docking Simulation , Niemann-Pick C1 Protein/chemistry , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/metabolism
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