Chiu Din-Chi, Lin Tzu-Chen, Huang Wen-I, Cheng Ting-Jen, Tsai Keng-Chang, Fang Jim-Min
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
Org Biomol Chem. 2017 Nov 29;15(46):9910-9922. doi: 10.1039/c7ob02374j.
Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5-9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3 + 2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits the H275Y mutant with an IC value of 35 nM, which is better than the WSN virus by 9 fold.
帕拉米韦是流感临床治疗中一种有效的抗流感药物，但其对H275Y突变体的疗效降低。先前报道的突变神经氨酸酶（NA）中抑制剂的共晶体结构表明，疏水侧链应是结合亲和力降低的根源。相比之下，具有亲水性甘油侧链的扎那米韦对H275Y NA仍具有高亲和力。因此，我们设计了五种带有亲水性二醇或甘油侧链的帕拉米韦类似物（5-9），并评估了它们在抗流感活性中的作用，特别是对H275Y突变体的作用。合成序列涉及烯烃与腈氧化物之间（3 + 2）环加成反应的关键步骤，以构建带有所需亲水性侧链和其他合适官能团的帕拉米韦支架。分子对接实验表明，亲水性侧链可与H275Y NA活性位点中易位的Glu-276残基提供额外的氢键。因此，H275Y突变体对带有亲水性侧链的帕拉米韦类似物可能比野生型病毒更敏感。值得注意的是，带有甘油侧链的帕拉米韦类似物以35 nM的IC值抑制H275Y突变体，比WSN病毒好9倍。
