Medizinische Chemie, Universität Heidelberg, Heidelberg, Germany.
Bioorg Med Chem. 2011 Jul 1;19(13):4067-74. doi: 10.1016/j.bmc.2011.05.015. Epub 2011 May 18.
The development of small molecule inhibitors of the viral protease is of considerable interest for the treatment of emergent flaviviral diseases such as Dengue or West Nile fever. Until today little progress has been made in finding drug-like compounds that inhibit the protease and provide a starting point for lead optimization. We describe here the initial steps of a drug discovery effort that focused on the styryl pharmacophore, combined with a ketoamide function to serve as electrophilic trap for the catalytic serine. This resulted in a fragment-like lead compound with reasonable target affinity and good ligand efficiency, which was extensively modified to explore structure-activity relationships. Selected compounds were cross-tested against the West Nile virus protease and thrombin, indicating that selectivity for one or more flaviviral proteases can be achieved. Finally, the antiviral activity of several protease inhibitors was confirmed in a cell-culture model of Dengue virus replication. The SAR presented here may serve as starting point for further drug discovery efforts with the aim of targeting flaviviral proteases.
小分子病毒蛋白酶抑制剂的开发对于治疗登革热或西尼罗河热等新兴的黄病毒病具有重要意义。迄今为止，在寻找抑制蛋白酶并为先导化合物优化提供起点的类药化合物方面进展甚微。我们在这里描述了一项药物发现工作的初步步骤，该工作集中在 styryl 药效团上，并结合了 ketoamide 功能，作为催化丝氨酸的亲电陷阱。这导致了具有合理靶标亲和力和良好配体效率的片段样先导化合物，对其进行了广泛的修饰以探索构效关系。选择的化合物被交叉测试针对西尼罗河病毒蛋白酶和凝血酶，表明可以实现对一种或多种黄病毒蛋白酶的选择性。最后，几种蛋白酶抑制剂的抗病毒活性在登革热病毒复制的细胞培养模型中得到了证实。本文中呈现的 SAR 可以作为进一步药物发现工作的起点，旨在针对黄病毒蛋白酶。
