Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens

被引:81
作者
Shiryaev, Sergey A.
Remacle, Albert G.
Ratnikov, Boris I.
Nelson, Nicholas A.
Savinov, Alexei Y.
Wei, Ge
Bottini, Massimo
Rega, Michele F.
Parent, Amelie
Desjardins, Roxane
Fugere, Martin
Day, Robert
Sabet, Mojgan
Pellecchia, Maurizio
Liddington, Robert C.
Smith, Jeffrey W.
Mustelin, Tomas
Guiney, Donald G.
Lebl, Michal
Strongin, Alex Y.
机构
[1] Burnham Inst Med Res, La Jolla, CA 92037 USA
[2] Illumina Inc, San Diego, CA 92121 USA
[3] Univ Sherbrooke, Dept Pharmacol, Sherbrooke, PQ J1H SN4, Canada
[4] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA
关键词
D O I
10.1074/jbc.M703847200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pathogens or their toxins, including influenza virus, Pseudomonas, and anthrax toxins, require processing by host proprotein convertases (PCs) to enter host cells and to cause disease. Conversely, inhibiting PCs is likely to protect host cells from multiple furin-dependent, but otherwise unrelated, pathogens. To determine if this concept is correct, we designed specific nanomolar inhibitors of PCs modeled from the extended cleavage motif TPQRERRRKKR down arrow GL of the avian influenza H5N1 hemagglutinin. We then confirmed the efficacy of the inhibitory peptides in vitro against the fluorescent peptide, anthrax protective antigen (PA83), and influenza hemagglutinin substrates and also in mice in vivo against two unrelated toxins, anthrax and Pseudomonas exotoxin. Peptides with Phe/Tyr at P1' were more selective for furin. Peptides with P1' Thr were potent against multiple PCs. Our strategy of basing the peptide sequence on a furin cleavage motif known for an avian flu virus shows the power of starting inhibitor design with a known substrate. Our results confirm that inhibiting furin-like PCs protects the host from the distinct furin-dependent infections and lay a foundation for novel, host cell-focused therapies against acute diseases.
引用
收藏
页码:20847 / 20853
页数:7
相关论文
共 35 条
[1]   Implication of the proprotein convertases furin, PC5 and PC7 in the cleavage of surface glycoproteins of Hong Kong, Ebola and respiratory syncytial viruses:: a comparative analysis with fluorogenic peptides [J].
Basak, A ;
Zhong, M ;
Munzer, JS ;
Chrétien, M ;
Seidah, NG .
BIOCHEMICAL JOURNAL, 2001, 353 :537-545
[2]   Synthesis and characterization of supramolecular nanostructures of carbon nanotubes and ruthenium-complex luminophores [J].
Bottini, M ;
Magrini, A ;
Di Venere, A ;
Bellucci, S ;
Dawson, MI ;
Rosato, N ;
Bergamaschi, A ;
Mustelin, T .
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY, 2006, 6 (05) :1381-1386
[3]   Anthrax toxin receptor proteins [J].
Bradley, KA ;
Young, JAT .
BIOCHEMICAL PHARMACOLOGY, 2003, 65 (03) :309-314
[4]   Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation [J].
Chen, J ;
Lee, KH ;
Steinhauer, DA ;
Stevens, DJ ;
Skehel, JJ ;
Wiley, DC .
CELL, 1998, 95 (03) :409-417
[5]   Furin-mediated cleavage of Pseudomonas exotoxin-derived chimeric toxins [J].
Chiron, MF ;
Fryling, CM ;
FitzGerald, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (50) :31707-31711
[6]   Anthrax toxin [J].
Collier, RJ ;
Young, JAT .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2003, 19 :45-70
[7]   A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor [J].
Doranz, BJ ;
GrovitFerbas, K ;
Sharron, MP ;
Mao, SH ;
Goetz, MB ;
Daar, ES ;
Doms, RW ;
OBrien, WA .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (08) :1395-1400
[8]   Anti-ETA IgG neutralizes the effects of Pseudomonas aeruginosa exotoxin A [J].
Fogle, MR ;
Griswold, JA ;
Oliver, JW ;
Hamood, AN .
JOURNAL OF SURGICAL RESEARCH, 2002, 106 (01) :86-98
[9]   Efficient synthetic inhibitors of anthrax lethal factor [J].
Forino, M ;
Johnson, S ;
Wong, TY ;
Rozanov, DV ;
Savinov, AY ;
Li, W ;
Fattorusso, R ;
Becattini, B ;
Orry, AJ ;
Jung, DW ;
Abagyan, RA ;
Smith, JW ;
Alibek, K ;
Liddington, RC ;
Strongin, AY ;
Pellecchia, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (27) :9499-9504
[10]   Cutting back on pro-protein convertases:: the latest approaches to pharmacological inhibition [J].
Fugère, M ;
Day, R .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2005, 26 (06) :294-301