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The human mucus protease inhibitor and its mutants are novel defensive compounds against infection with influenza A and Sendai viruses
Author(s) -
Kido Hiroshi,
Beppu Yoshihito,
Imamura Yasuhiro,
Chen Ye,
Murakami Meiko,
Oba Kumiko,
Towatari Takae
Publication year - 1999
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/(sici)1097-0282(1999)51:1<79::aid-bip9>3.0.co;2-w
Subject(s) - chemistry , tryptase , infectivity , protease , sendai virus , glycoprotein , virus , viral envelope , influenza a virus , virology , slpi , microbiology and biotechnology , biology , biochemistry , enzyme , mast cell , immunology , inflammation
Tryptase Clara, a trypsin‐like protease localized exclusively in and secreted by Clara cells of the bronchial epithelium, is a prime host factor that processes viral envelope glycoproteins and determines the infectivity of influenza A and Sendai viruses (H. Kido, Y. Yokogoshi, K. Sakai, M. Tashiro, Y. Kishino, A. Fukutomi, and N. Katunuma, The Journal of Biological Chemistry, 1992, Vol. 267, pp. 13573–13579). We report here that human mucus protease inhibitor (MPI), a major inhibitor of granulocyte elastase in the lining fluid of the human respiratory tract, significantly inhibited induction of the infectivity of influenza A and Sendai viruses by tryptase Clara in vitro and multicycles of mouse‐adapted influenza A virus replication in rat lungs in vivo. Recombinant MPI and the C‐ but not the N‐terminal domain of MPI inhibited both the activity of tryptase Clara and the induction of virus infection by tryptase Clara. The 50% inhibitory concentrations of MPI and the C‐terminal domain peptide (Pro 50 –Ala 107 ) of MPI for tryptase Clara were 7.4 and 61.6 nM, respectively, with Sendai virus envelope glycoproteins as the substrate. Studies on deletion mutants of the C‐terminal domain of MPI revealed that the minimal size of MPI required for the inhibition of tryptase Clara is the peptide Lys 60 –Ala 107 . Studies involving site‐directed mutagenesis of the C‐terminal domain of MPI indicated that the Leu 72 –Met 73 site of MPI is the inhibitory site for tryptase Clara. Substitution of residue Leu 72 with a basic amino acid significantly increased in the inhibitory activity of the C‐terminal domain of MPI, but further substitution of residue Met 73 with various amino acids in these mutants reduced the inhibitory activity. Since there is evidence suggesting that the concentration of MPI in respiratory fluid is insufficient for prevention of virus infection, the administration of MPI, the recombinant C‐terminal domain of MPI, and their mutants, with residue Leu 72 substituted with residues Arg 72 and Lys 72 , may be useful for treatment of such pneumotropic virus infections. © 1999 John Wiley & Sons, Inc. Biopoly 51: 79–86, 1999