Structural and functional features of the polycationic peptide required for inhibition of herpes simplex virus invasion of cells.
Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) mediates initial virus contact with cells by binding to heparan sulfate (HS) chains. The synthetic peptide 137GSRVQIRCRFRNSTR151 overlapping a major part of the HS-binding site of gC inhibited HSV-1 infection and, to some extent, HSV-2 infection of cells. Experiments on mutant, glycosaminoglycan-deficient cells as well as the binding assays involving peptide and purified cell surface components identified HS, and, to a lesser degree, chondroitin sulfate as sites of peptide activity. Anti-HSV-1 activity of the peptide was due to (i) partial inhibition of virus binding to cells and (ii) arresting the virions, which managed to attach to the cells in the presence of peptide, at a step of initial relatively weak binding. Analysis of the ionic-strength dependence of the peptide-HS and the virus-HS interactions revealed that the more efficient inhibition by the peptide of HSV-1 than HSV-2 infectivity was due to a relatively high affinity of HSV-2 for HS, a feature of importance in overcoming the peptide block. Mutational analysis of viral gC and peptide variants identified, apart from basic amino acids, two hydrophobic residues Ile(142) and Phe(146) as important in maintaining the specific affinity of peptide for HS and, hence, its anti-HSV activity. These results could contribute to the development of anti-HSV compounds that target initial events in the virus-cell interaction.
Trybala
Edward
E
Department of Clinical Virology, Göteborg University, Guldhedsgatan 10B, S-413 46 Gothenburg, Sweden.
Olofsson
Sigvard
S
Mårdberg
Kristina
K
Svennerholm
Bo
B
Umemoto
Kimiko
K
Glorioso
Joseph C
JC
Bergström
Tomas
T
D000818:Animals; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D006023:Glycoproteins / Q000737:chemistry; D006497:Heparan Sulfate / Q000737:chemistry; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D000071228:Polyelectrolytes; D014759:Viral Envelope Proteins / Q000187:drug effects / Q000378:metabolism*
D006023:Glycoproteins; D006497:Heparan Sulfate; D010455:Peptides; D011073:Polyamines; D000071228:Polyelectrolytes; D014759:Viral Envelope Proteins; C038535:glycoprotein gC, herpes simplex virus type 1