Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
J Pharm Sci. 2012 Oct;101(10):3896-905. doi: 10.1002/jps.23253. Epub 2012 Jul 11.
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.
利用空斑减少试验，研究了相对简单的双环醌类分子，以及共价连接到长多聚谷氨酸聚合物链上的多个拷贝，作为新型抗各种天然流感 A 病毒株抑制剂。与相应的母体分子相比，聚合物连接的抑制剂对人武汉流感株的效力要强得多（对于某些具有长间隔臂的化合物，其效力高两个数量级）。然而，与小分子前体相比，此类聚合抑制剂对人波多黎各和禽火鸡流感株的效力并没有提高。通过分子建模进一步探索这些观察结果表明，多价结合的益处存在以前未被认识到的不可预测性，这可能是由于聚合试剂对病毒靶标不易接近所致。
