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Antimicrobial Agents and Chemotherapy, March 2009, p. 987-996, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00793-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Multiple Peptides Homologous to Herpes Simplex Virus Type 1 Glycoprotein B Inhibit Viral Infection {triangledown}

Radeekorn Akkarawongsa,1 Nina E. Pocaro,3 Gary Case,3 Aaron W. Kolb,2 and Curtis R. Brandt1,2,4*

Program in Cell and Molecular Biology,1 Department of Ophthalmology and Visual Sciences,2 Biotechnology Center,3 Department of Medical Microbiology and Immunology, University of Wisconsin—Madison, Madison, Wisconsin 537064

Received 17 June 2008/ Returned for modification 18 July 2008/ Accepted 12 December 2008

The 773-residue ectodomain of the herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) has been resistant to the use of mutagenic strategies because the majority of the induced mutations result in defective proteins. As an alternative strategy for the identification of functionally important regions and novel inhibitors of infection, we prepared a library of overlapping peptides homologous to the ectodomain of gB and screened for the ability of the peptides to block infection. Seven of 138 15-mer peptides inhibited infection by more than 50% at a concentration of 100 µM. Three peptides (gB94, gB122, and gB131) with 50% effective concentrations (EC50s) below 20 µM were selected for further studies. The gB131 peptide (residues 681 to 695 in HSV-1 gB [gB-1]) was a specific entry inhibitor (EC50, ~12 µM). The gB122 peptide (residues 636 to 650 in gB-1) blocked viral entry (EC50, ~18 µM), protected cells from infection (EC50, ~72 µM), and inactivated virions in solution (EC50, ~138 µM). We were unable to discern the step or steps inhibited by the gB94 peptide, which is homologous to residues 496 to 510 in gB-1. Substitution of a tyrosine in the gB122 peptide (Y640 in full-length gB-1) reduced the antiviral activity eightfold, suggesting that this residue is critical for inhibition. This peptide-based strategy could lead to the identification of functionally important regions of gB or other membrane proteins and identify novel inhibitors of HSV-1 entry.

* Corresponding author. Mailing address: Department of Ophthalmology and Visual Sciences, 6630 Medical Sciences Center, 1300 University Ave., Madison, WI 53706. Phone: (608) 262-8054. Fax: (608) 262-0479. E-mail: crbrandt{at}wisc.edu

{triangledown} Published ahead of print on 22 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 987-996, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00793-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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