Cell Penetrable Human scFv Specific to Middle Domain of Matrix Protein-1 Protects Mice from Lethal Influenza

Viruses

Fonthip Dong-din-on¹  Pattra Moonjit²  Preeda Lertwatcharasarakul²  Thaweesak Songserm²  Potjanee Srimanote³  Tippawan Pissawong⁴  Kanyarat Thueng-in⁴  Wanpen Chaicumpa⁴  Jeeraphong Thanongsaksrikul⁴  Watee Seesuay⁴ 

[1] Center for Agricultural Biotechnology, Kasetsart University, Kamphaeng Saen Campus,Nakhon Pathom 73140, Thailand;Department of Veterinary Pathology, Faculty of Veterinary Medicine, Kasetsart University, Kamphaeng Saen Campus, Nakhon Pathom 73140, Thailand;Graduate Program in Biomedical Science, Faculty of Allied Health Sciences,Thammasat University, Pathumthani 12120, Thailand;Laboratory for Research and Technology Development, Department of Parasitology,and Center of Excellence on Therapeutic Proteins and Antibody Engineering,Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;

关键词: Cell penetrating antibody;    H5N1;    human ScFv;    influenza;    influenza virus;    matrix protein-1 (M1);    middle domain of M1;    molecular docking;    phage display;    transbody;   

DOI  :  10.3390/v7010154

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown