Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction
Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction
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DOI：
10.1016/j.bmcl.2019.07.027
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发表时间：
2019-09-01
影响因子：
2.7
通讯作者：
Hantani, Yoshiji
中科院分区：
文献类型：
--
作者：
Kawashita, Seiji;Aoyagi, Koichi;Hantani, Yoshiji
人们热切期待PD-1/PD-L1小分子抑制剂的开发，以用于癌症的治疗。我们重点研究了已报道的小分子配体和HPD-L1同源二聚体三元络合物结构的对称性，并设计了部分或完全对称的化合物用于更有效的抑制剂。新化合物的设计是以我们的假设为指导的，即所设计的对称化合物将诱导(A)Tyr56蛋白残基的侧链翻转形成新的空腔。所设计的化合物4与HPD-L1的结合亲和力显著提高，并在生理条件下具有PD-1/PD-L1抑制活性。在混合淋巴细胞反应实验中，化合物4也显示出剂量依赖性的增加干扰素-γ的分泌水平。这些结果不仅表明了用小分子靶向PD-1/PD-L1途径的可行性，而且说明了基于对称性的配体设计作为靶向蛋白质-蛋白质相互作用稳定剂的一种有吸引力的方法的适用性。
The development of small molecule inhibitors of PD-1/PD-L1 is eagerly anticipated for treatment of cancer. We focused on the symmetry of the ternary complex structure of reported small molecule ligands and hPD-L1 homodimers, and designed partially- or fully-symmetric compounds for more potent inhibitors. The design of the new compounds was guided by our hypothesis that the designed symmetric compound would induce a flip of sidechain of (A)Tyr56 protein residue to form a new cavity. The designed compound 4 exhibited substantially increased binding affinity to hPD-L1, as well as PD-1/PD-L1 inhibitory activity in physiological conditions. Compound 4 also showed a dose-dependent increase in IFN-gamma secretion levels in a mixed lymphocyte reaction assay. These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers.