Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread.
Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.
Cheshenko
Natalia
N
Department of Pediatrics, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1657, New York, NY 10029, USA.
Keller
Marla J
MJ
MasCasullo
Veronica
V
Jarvis
Gary A
GA
Cheng
Hui
H
John
Minnie
M
Li
Jin-Hua
JH
Hogarty
Kathleen
K
Anderson
Robert A
RA
Waller
Donald P
DP
Zaneveld
Lourens J D
LJ
Profy
Albert T
AT
Klotman
Mary E
ME
Herold
Betsy C
BC
D000891:Anti-Infective Agents, Local / Q000494:pharmacology* / Q000627:therapeutic use*; D001826:Body Fluids / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002584:Cervix Uteri / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology*; D018258:Herpesvirus 2, Human / Q000472:pathogenicity; D049670:History, 17th Century; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D011134:Polysaccharides / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D014759:Viral Envelope Proteins / Q000378:metabolism*; D010948:Viral Plaque Assay
D000891:Anti-Infective Agents, Local; D016207:Cytokines; D011134:Polysaccharides; D014759:Viral Envelope Proteins; C044525:glycoprotein B, herpes simplex virus type 2