title: Digallate dimers of (-)-epigallocatechin gallate inactivate herpes simplex virus.
abstract: Topical microbicides are potentially an alternative method to vaccines for reducing the spread of herpes simplex virus (HSV). We have previously shown (S. Liu et al., Biochim. Biophys. Acta 1723:270-281, 2005) that the catechin (-)-epigallocatechin gallate (EGCG) inactivates HSV at neutral pH; however, to function in the female genital tract EGCG must also be effective at acidic pH. EGCG inactivated HSV-1 and HSV-2 at pH 8.0 by 3 log(10) to 4 log(10) but was ineffective at pH 5.7. The EGCG digallate dimers theasinensin A, P2, and theaflavin-3,3'-digallate (TF-3) inactivated both viruses by 3 log(10) to 4 log(10) at pH 5.7 and as much as 5 log(10) at pH 8.0. TF-3 inactivated HSV-1 and HSV-2 by 4 to 5 log(10) in the pH range of 4.0 to 5.7. Dimers with one gallate moiety had antiviral activity intermediate between the activities of EGCG and digallate dimers. Confocal and electron microscopy showed that theasinensin A did not damage Vero cells. All EGCG dimers inactivated enveloped viruses with class I, class II, and class III (HSV-1, HSV-2) fusion proteins more effectively than did monomeric EGCG. EGCG had no activity against the nonenveloped viruses tested, but TF-3 reduced the titer of 4 of 5 nonenveloped viruses by ≅2 to 3.5 log(10). Results also showed that HSV-1 glycoprotein B (gB) was aggregated more rapidly by theasinensin A than EGCG, which, when taken together with the nonenveloped virus data, suggests that dimers may inhibit the function of viral proteins required for infectivity. Digallate dimers of EGCG appear to have excellent potential as microbicidal agents against HSV at acidic and neutral pHs.
authors.affiliation: Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA. chisi@rcn.com
authors.forename: Charles E
authors.initials: CE
authors.lastname: Isaacs
authors.forename: Weimin
authors.initials: W
authors.lastname: Xu
authors.forename: George
authors.initials: G
authors.lastname: Merz
authors.forename: Sharon
authors.initials: S
authors.lastname: Hillier
authors.forename: Lisa
authors.initials: L
authors.lastname: Rohan
authors.forename: Guang Y
authors.initials: GY
authors.lastname: Wen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D053630:Depsides / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006561:Herpes Simplex / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000648:ultrastructure; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008854:Microscopy, Electron; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells; D038301:Virus Inactivation / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001578:Benzopyrans; D053630:Depsides; D010636:Phenols; C481298:theasinensin A; C067648:digallic acid; D005707:Gallic Acid; D002392:Catechin; C045651:epigallocatechin gallate