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Co-immunoprecipitation of the Mouse Mx1 Protein with the Influenza A Virus Nucleoprotein
Published on: April 21, 2015
Cell penetrable human scFv specific to middle domain of matrix protein-1 protects mice from lethal influenza
Fonthip Dong-din-on1, Thaweesak Songserm2, Tippawan Pissawong3
1Center for Agricultural Biotechnology, Kasetsart University, Kamphaeng Saen Campus, Nakhon Pathom 73140, Thailand. fddvt66@outlook.com.
Abstract:
A new anti-influenza remedy that can tolerate the virus antigenic variation is needed. Influenza virus matrix protein-1 (M1) is highly conserved and pivotal for the virus replication cycle: virus uncoating, assembly and budding. An agent that blocks the M1 functions should be an effective anti-influenza agent. In this study, human scFv that bound to recombinant M1 middle domain (MD) and native M1 of A/H5N1 was produced. Phage mimotope search and computerized molecular docking revealed that the scFv bound to the MD conformational epitope formed by juxtaposed helices 7 and 9 of the M1. The scFv was linked molecularly to a cell penetrable peptide, penetratin (PEN). The PEN-scFv (transbody), when used to treat the cells pre-infected with the heterologous clade/subclade A/H5N1 reduced the viral mRNA intracellularly and in the cell culture fluids. The transbody mitigated symptom severity and lung histopathology of the H5N1 infected mice and caused reduction of virus antigen in the tissues as well as extricated the animals from the lethal challenge in a dose dependent manner. The transbody specific to the M1 MD, either alone or in combination with the cognate human scFvs specific to other influenza virus proteins, should be an effective, safe and mutation tolerable anti-influenza agent.
Insights
A novel transbody targeting conserved influenza M1 protein shows promise as a mutation-tolerant anti-influenza agent. This therapy reduced viral load and protected mice from lethal H5N1 infection.
Area of Science:
- Virology
- Immunology
- Drug Discovery
Background:
- Influenza virus antigenic variation necessitates new therapies.
- Influenza virus matrix protein-1 (M1) is a conserved target crucial for viral replication.
- Targeting M1 offers a strategy for broad-spectrum anti-influenza agents.
Purpose of the Study:
- To develop a novel therapeutic agent targeting the conserved M1 protein of the influenza virus.
- To evaluate the efficacy of a M1-specific single-chain variable fragment (scFv) linked to penetratin (PEN-scFv transbody) against H5N1 influenza.
- To assess the transbody's ability to overcome viral antigenic drift.
Main Methods:
- Production of human scFv binding to M1 middle domain (MD) and native M1.
- Identification of the binding epitope using phage mimotope and molecular docking.
- Construction and application of the PEN-scFv transbody in cell culture and a mouse model of H5N1 infection.
Main Results:
- The scFv recognized a conformational epitope on M1 MD.
- The PEN-scFv transbody significantly reduced viral mRNA in infected cells and cell culture fluids.
- Transbody treatment mitigated H5N1-induced symptoms, lung pathology, and mortality in mice in a dose-dependent manner.
Conclusions:
- The M1-targeting transbody is a potent and mutation-tolerant anti-influenza therapeutic candidate.
- This approach offers a potential strategy against antigenically diverse influenza strains.
- Further development of M1-specific transbody therapies holds promise for influenza treatment.
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