Liu Bin, Joseph Rhoda W, Dorsey Bruce D, Schiksnis Robert A, Northrop Katrina, Bukhtiyarova Marina, Springman Eric B
Locus Pharmaceuticals, Inc., Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA.
Bioorg Med Chem Lett. 2009 Oct 1;19(19):5693-7. doi: 10.1016/j.bmcl.2009.08.018. Epub 2009 Aug 8.
A series of substituted biphenyl ethylene ether compounds has been designed to target the gp41N-trimer in order to inhibit formation of the six-helical bundle that represents the end state of gp41-mediated viral fusion. A size exclusion HPLC based helical bundle formation (HBF) assay was developed to evaluate in vitro inhibitory affinity of the inhibitors. The most potent compound 1 had an IC(50) of 31microM. The binding of compound 1 to the proposed hydrophobic pocket of gp41 was further validated by site-directed peptide mutagenesis experiments.
为了靶向gp41N-三聚体以抑制六螺旋束的形成（六螺旋束代表gp41介导的病毒融合的终末状态），设计了一系列取代的联苯乙烯醚化合物。开发了一种基于尺寸排阻高效液相色谱的螺旋束形成（HBF）测定法，以评估抑制剂的体外抑制亲和力。最有效的化合物1的IC50为31μM。通过定点肽诱变实验进一步验证了化合物1与gp41拟疏水口袋的结合。
