Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection

被引:174
作者
Malakhov, MP
Aschenbrenner, LM
Smee, DF
Wandersee, MK
Sidwell, RW
Gubareva, LV
Mishin, VP
Hayden, FG
Kim, DH
Ing, A
Campbell, ER
Yu, M
Fang, F
机构
[1] NexBio Inc, San Diego, CA 92121 USA
[2] Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA
[3] Univ Virginia, Dept Internal Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA
关键词
D O I
10.1128/AAC.50.4.1470-1479.2006
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Influenza is a highly infectious disease characterized by recurrent annual epidemics and unpredictable major worldwide pandemics. Rapid spread of the highly pathogenic avian H5N1 strain and escalating human infections by the virus have set off the alarm for a global pandemic. To provide an urgently needed alternative treatment modality for influenza, we have generated a recombinant fusion protein composed of a sialidase catalytic domain derived from Actinomyces viscosus fused with a cell surface-anchoring sequence. The sialidase fusion protein is to be applied topically as an inhalant to remove the influenza viral receptors, sialic acids, from the airway epithelium. We demonstrate that a sialidase fusion construct, DAS181, effectively cleaves sialic acid receptors used by both human and avian influenza viruses. The treatment provides long-lasting effect and is nontoxic to the cells. DAS181 demonstrated potent antiviral and cell protective efficacies against a panel of laboratory strains and clinical isolates of IFV A and IFV B, with virus replication inhibition 50% effective concentrations in the range of 0.04 to 0.9 nM. Mouse and ferret studies confirmed significant in vivo efficacy of the sialidase fusion in both prophylactic and treatment modes.
引用
收藏
页码:1470 / 1479
页数:10
相关论文
共 58 条
  • [1] Comparative enzymology, biochemistry and pathophysiology of human exo-α-sialidases (neuraminidases)
    Achyuthan, KE
    Achyuthan, AM
    [J]. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY, 2001, 129 (01): : 29 - 64
  • [2] RED-CELLS BOUND TO INFLUENZA-VIRUS N9 NEURAMINIDASE ARE NOT RELEASED BY THE N9 NEURAMINIDASE ACTIVITY
    AIR, GM
    LAVER, WG
    [J]. VIROLOGY, 1995, 211 (01) : 278 - 284
  • [3] GLYCOSPHINGOLIPID RECEPTORS FOR PSEUDOMONAS-AERUGINOSA
    BAKER, N
    HANSSON, GC
    LEFFLER, H
    RIISE, G
    SVANBORGEDEN, C
    [J]. INFECTION AND IMMUNITY, 1990, 58 (07) : 2361 - 2366
  • [4] Adherence of Streptococcus pneumoniae to respiratory epithelial cells is inhibited by sialylated oligosaccharides
    Barthelson, R
    Mobasseri, A
    Zopf, D
    Simon, P
    [J]. INFECTION AND IMMUNITY, 1998, 66 (04) : 1439 - 1444
  • [5] Current concepts - Avian influenza A (H5N1) infection in humans
    Beigel, H
    Farrar, H
    Han, AM
    Hayden, FG
    Hyer, R
    de Jong, MD
    Lochindarat, S
    Tien, NTK
    Hien, NT
    Hien, TT
    Nicoll, A
    Touch, S
    Yuen, KY
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2005, 353 (13) : 1374 - 1385
  • [6] BERGELSON LD, 1982, EUR J BIOCHEM, V128, P467
  • [7] The evolution of H5N1 influenza viruses in ducks in southern China
    Chen, H
    Deng, G
    Li, Z
    Tian, G
    Li, Y
    Jiao, P
    Zhang, L
    Liu, Z
    Webster, RG
    Yu, K
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (28) : 10452 - 10457
  • [8] SUBSTRATE-SPECIFICITY OF NEURAMINIDASES
    DRZENIEK, R
    [J]. HISTOCHEMICAL JOURNAL, 1973, 5 (03): : 271 - 290
  • [9] SIALIC-ACID IS CLEAVED FROM GLYCOCONJUGATES AT THE CELL-SURFACE WHEN INFLUENZA-VIRUS NEURAMINIDASES ARE EXPRESSED FROM RECOMBINANT VACCINIA VIRUSES
    ELS, MC
    LAVER, WG
    AIR, GM
    [J]. VIROLOGY, 1989, 170 (01) : 346 - 351
  • [10] Specific binding of Haemophilus influenzae to minor gangliosides of human respiratory epithelial cells
    Fakih, MG
    Murphy, TF
    Pattoli, MA
    Berenson, CS
    [J]. INFECTION AND IMMUNITY, 1997, 65 (05) : 1695 - 1700