Inhibition of herpes simplex virus by polyamines.
BACKGROUND
Herpes simplex virus (HSV) establishes latent infection in humans with periodic reactivation. Acyclovir, valacyclovir and foscarnet are in medical use today against HSV type-1 (HSV-1) and type-2 (HSV-2), inhibiting the DNA synthesis of the viruses. Additional drugs that will affect the growth of these viruses by other mechanisms and also decrease the frequency of appearance of drug-resistant mutants are required.


METHODS
Cationic polysaccharides were synthesized by conjugation of various oligoamines to oxidized polysaccharides by reductive amination. Polycations of dextran, pullulan and arabinogalactan were grafted with oligoamines of 2-4 amino groups forming Schiff-base imine-based conjugates followed by reduction with borohydride to obtain the stable amine-based conjugate. Evaluation of toxicity to BS-C-1 cells and antiviral activity against HSV-1 and HSV-2 of the different compounds was performed in vitro by a semiquantitative assay. A quantitative study with a selected compound followed.


RESULTS
Structure-activity relationship studies showed that the nature of the grafted oligoamine of the polycation plays an essential role in the antiviral activity against HSV-1 and HSV-2. Dextran-propan-1,3-diamine (DPD) was found to be the most potent of all the compounds examined. DPD did not decrease the infectivity of HSV upon direct exposure to the virions. The growth of HSV was significantly inhibited when DPD was added to the host cells 1 h prior to infection, thus preventing the adsorption and penetration of the virus into the cells.


CONCLUSIONS
Our in vitro data warrant clinical investigation. DPD could have an advantage as a topical application in combination therapy of HSV lesions.
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, the Hebrew University, Jerusalem, Israel.
Ira
I
Yudovin-Farber
Irina
I
Gurt
Ronen
R
Hope
Abraham J
AJ
Domb
Ehud
E
Katz
D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D018139:Simplexvirus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects
D011073:Polyamines