Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide

被引:22
作者
Altmann, S. E. [2 ]
Jones, J. C. [2 ]
Schultz-Cherry, S. [2 ,3 ]
Brandt, C. R. [1 ,2 ,3 ]
机构
[1] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA
[2] Univ Wisconsin, Sch Med & Publ Hlth, Microbiol Doctoral Training Program, Madison, WI 53706 USA
[3] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med Microbiol & Immunol, Madison, WI 53706 USA
基金
美国国家卫生研究院;
关键词
Antiviral peptide; Vaccinia virus; Virus entry; Entry blocker; Fusion; EB peptide; CELL-PENETRATING PEPTIDES; VIRION MEMBRANE-PROTEIN; STRAIN L CELLS; SMALLPOX VACCINATION; SIGNAL RECOGNITION; ESSENTIAL COMPONENT; STRUCTURAL BASIS; POXVIRUS ENTRY; TAT PROTEIN; FUSION;
D O I
10.1016/j.virol.2009.03.023
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Concerns about the possible use of Variola virus, the Causative agent of smallpox, as a weapon for bioterrorism have led to renewed efforts to identify new antivirals against orthopoxviruses. We identified a peptide, EB, which inhibited infection by Vaccinia virus with an EC50 of 15 mu M. A control peptide, EBX, identical in composition to EB but differing in sequence, was inactive (EC50>200 mu M), indicating sequence specificity. The inhibition was reversed upon removal of the peptide, and EB treatment had no effect on the physical integrity of virus particles as determined by election microscopy. Viral adsorption was unaffected by the presence of EB, and the addition of EB post-entry had no effect on viral titers or on early gene expression. The addition of EB post-adsorption resulted in the inhibition of beta-galactosidase expression from an early viral Promoter with an EC50 of 45 mu M. A significant reduction in virus entry was detected in the presence of the peptide when the number of viral cores released into the cytoplasm was quantified. Electron microscopy indicated that 88% of the virions remained on the surface of cells in the presence of EB, compared to 37% in the control (p <0.001). EB also blocked fusion-from-within, suggesting that virus infection is inhibited at the fusion step. Analysis of EB derivatives suggested that peptide length may be important for the activity of EB. The EB peptide is, to our knowledge, the first known small molecule inhibitor of Vaccinia virus entry. (c) 2009 Elsevier Inc. All rights reserved.
引用
收藏
页码:248 / 259
页数:12
相关论文
共 68 条
[1]   Corneal toxicity of cell-penetrating peptides that inhibit Herpes simplex virus entry [J].
Akkarawongsa, Radeekorn ;
Cullinan, Amy E. ;
Zinkel, Andrew ;
Clarin, Joshua ;
Brandt, Curtis R. .
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, 2006, 22 (04) :279-289
[2]   MODE OF ENTRY OF VACCINIA VIRUS INTO L CELLS [J].
ARMSTRONG, JA ;
METZ, DH ;
YOUNG, MR .
JOURNAL OF GENERAL VIROLOGY, 1973, 21 (DEC) :533-537
[3]   Safety profile of smallpox vaccine: Insights from the laboratory worker smallpox vaccination program [J].
Baggs, J ;
Chen, RT ;
Damon, IK ;
Rotz, L ;
Allen, C ;
Fullerton, KE ;
Casey, C ;
Nordenberg, D ;
Mootrey, G .
CLINICAL INFECTIOUS DISEASES, 2005, 40 (08) :1133-1140
[4]   Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections [J].
Baker, R ;
Bray, M ;
Huggins, JW .
ANTIVIRAL RESEARCH, 2003, 57 (1-2) :13-23
[5]   Vaccinia virus L1 protein is required for cell entry and membrane fusion [J].
Bisht, Himani ;
Weisberg, Andrea S. ;
Moss, Bernard .
JOURNAL OF VIROLOGY, 2008, 82 (17) :8687-8694
[6]   Vaccinia virus F9 virion membrane protein is required for entry but not virus assembly, in contrast to the related L1 protein [J].
Brown, Erica ;
Senkevich, Tatiana G. ;
Moss, Bernard .
JOURNAL OF VIROLOGY, 2006, 80 (19) :9455-9464
[7]   Efficacy of oral active ether lipid analogs of cidofovir in a lethal mousepox model [J].
Buller, RM ;
Owens, G ;
Schriewer, J ;
Melman, L ;
Beadle, JR ;
Hostetler, KY .
VIROLOGY, 2004, 318 (02) :474-481
[8]   Peptides containing membrane-transiting motifs inhibit virus entry [J].
Bultmann, H ;
Brandt, CR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (39) :36018-36023
[9]   Modified FGF4 signal peptide inhibits entry of herpes simplex virus type 1 [J].
Bultmann, H ;
Busse, JS ;
Brandt, CR .
JOURNAL OF VIROLOGY, 2001, 75 (06) :2634-2645
[10]   Addition of a C-terminal cysteine improves the anti-herpes simplex virus activity of a peptide containing the human immunodeficiency virus type 1 TAT protein transduction domain [J].
Bultmann, Hermann ;
Teuton, Jeremy ;
Brandt, Curtis R. .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2007, 51 (05) :1596-1607