Conjugating drug candidates to polymeric chains does not necessarily enhance anti-influenza activity.
Using the plaque reduction assay, relatively simple bicyclic quinone molecules, as well as multiple copies thereof covalently attached to a long polyglutamate-based polymeric chain, were examined as new inhibitors of various naturally occurring strains of influenza A virus. The polymer-conjugated inhibitors were found to have a far greater potency (for some as high as two orders of magnitude when a long spacer arm was employed) than their corresponding parent molecules against the human Wuhan influenza strain. However, such polymeric inhibitors failed to exhibit higher potency compared with their small molecule predecessors against the human Puerto Rico and avian turkey influenza strains. These observations, further explored by means of molecular modeling, reveal the previously unrecognized unpredictability of the benefits of multivalency, possibly because of poor accessibility of the viral targets to polymeric agents.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Alyssa M
AM
Larson
Hongmei
H
Wang
Yang
Y
Cao
Taijiao
T
Jiang
Jianzhu
J
Chen
Alexander M
AM
Klibanov
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001717:Birds; D002460:Cell Line; D004285:Dogs; D004357:Drug Synergism; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D005585:Influenza in Birds / Q000188:drug therapy / Q000821:virology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000821:virology; D011099:Polyglutamic Acid / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D011108:Polymers; D011809:Quinones; D011099:Polyglutamic Acid