Bifunctional polymeric inhibitors of human influenza A viruses.
OBJECTIVE
New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1 + 2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses.


METHODS
Individually or together, 1 and 2 were covalently bonded to the polymer. The antiviral potencies of the resultant poly-1, poly-2, poly-(1 + 2), and poly-1 + poly-2, as well as 1 and 2, were assessed using plaque reduction assay.


RESULTS
Attaching 1 to the polymer improved at best millimolar IC(50) values over three orders of magnitude. While 2 exhibited micromolar IC(50) values, poly-2 was >100-fold even more potent. The IC(50) of poly-(1 + 2) against the wild-type strain was >300-fold and approximately 17-fold better than of poly-1 and poly-2, respectively. In contrast, the potency of poly-(1 + 2) vs. poly-2 against the mutant strain merely doubled. The mixture of poly-1 + poly-2 inhibited both viral strains similarly to poly-2.


CONCLUSIONS
The bifunctional poly-(1 + 2) acts synergistically against the wild-type influenza virus, but not against its drug-resistant mutant, as compared to a physical mixture of the monofunctional poly-1 and poly-2.
Haldar
Jayanta
J
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Alvarez de Cienfuegos
Luis
L
Tumpey
Terrence M
TM
Gubareva
Larisa V
LV
Chen
Jianzhu
J
Klibanov
Alexander M
AM
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000138:chemical synthesis*; D002460:Cell Line; D002642:Chick Embryo; D004285:Dogs; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development; D007251:Influenza, Human / Q000517:prevention & control / Q000821:virology; D020128:Inhibitory Concentration 50; D009976:Orthomyxoviridae Infections / Q000517:prevention & control / Q000821:virology; D011108:Polymers / Q000008:administration & dosage* / Q000138:chemical synthesis*; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D011108:Polymers