Article ; Online: Mutations in the Fusion Protein of Measles Virus That Confer Resistance to the Membrane Fusion Inhibitors Carbobenzoxy-d-Phe-l-Phe-Gly and 4-Nitro-2-Phenylacetyl Amino-Benzamide.
2017 Volume 91, Issue 23
Abstract: The inhibitors carbobenzoxy (Z)-d-Phe-l-Phe-Gly (fusion inhibitor peptide [FIP]) and 4-nitro-2 ... viruses that were resistant to the inhibitory effects of Z-d-Phe-l-Phe-Gly. These 10 mutations were ... formation mediated by measles virus (MeV). Other homologues, such as Z-d-Phe, are less effective but may act ...
| Abstract | The inhibitors carbobenzoxy (Z)-d-Phe-l-Phe-Gly (fusion inhibitor peptide [FIP]) and 4-nitro-2-phenylacetyl amino-benzamide (AS-48) have similar efficacies in blocking membrane fusion and syncytium formation mediated by measles virus (MeV). Other homologues, such as Z-d-Phe, are less effective but may act through the same mechanism. In an attempt to map the site of action of these inhibitors, we generated mutant viruses that were resistant to the inhibitory effects of Z-d-Phe-l-Phe-Gly. These 10 mutations were localized to the heptad repeat B (HRB) region of the fusion protein, and no changes were observed in the viral hemagglutinin, which is the receptor attachment protein. Mutations were validated in a luciferase-based membrane fusion assay, using transfected fusion and hemagglutinin expression plasmids or with syncytium-based assays in Vero, Vero-SLAM, and Vero-Nectin 4 cell lines. The changes I452T, D458N, D458G/V459A, N462K, N462H, G464E, and I483R conferred resistance to both FIP and AS-48 without compromising membrane fusion. The inhibitors did not block hemagglutinin protein-mediated binding to the target cell. Edmonston vaccine/laboratory and IC323 wild-type strains were equally affected by the inhibitors. Escape mutations were mapped upon a three-dimensional (3D) structure modeled from the published crystal structure of parainfluenzavirus 5 fusion protein. The most effective mutations were situated in a region located near the base of the globular head and its junction with the alpha-helical stalk of the prefusion protein. We hypothesize that the fusion inhibitors could interfere with the structural changes that occur between the prefusion and postfusion conformations of the fusion protein. |
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| MeSH term(s) | Animals ; Antiviral Agents/pharmacology ; Benzamides/pharmacology ; Chlorocebus aethiops ; Hemagglutinins, Viral/genetics ; Hemagglutinins, Viral/metabolism ; Measles virus/drug effects ; Measles virus/genetics ; Membrane Fusion/drug effects ; Models, Molecular ; Mutation ; Oligopeptides/pharmacology ; Protein Binding ; Vero Cells ; Viral Fusion Proteins/chemistry ; Viral Fusion Proteins/genetics ; Viral Fusion Proteins/metabolism ; Virus Internalization/drug effects |
| Chemical Substances | 4-nitro-2-phenylacetyl amino-benzamide ; Antiviral Agents ; Benzamides ; Hemagglutinins, Viral ; Oligopeptides ; Viral Fusion Proteins ; carbobenzoxyphenylalanyl-phenylalanyl-glycine (75539-79-6) |
| Language | English |
| Publishing date | 2017-11-14 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 80174-4 |
| ISSN | 1098-5514 ; 0022-538X |
| ISSN (online) | 1098-5514 |
| ISSN | 0022-538X |
| DOI | 10.1128/JVI.01026-17 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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