Yan Nicholas L, Wilson Ian A, Kelly Jeffery W
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Isr J Chem. 2023 Oct;63(10-11). doi: 10.1002/ijch.202300002. Epub 2023 Apr 12.
Stabilization of amyloidogenic immunoglobulin light chains (LCs) by binding of small molecule "kinetic stabilizers" is under development as a novel treatment for light chain amyloidosis. From a high-throughput screen, we previously identified 16 full-length (FL) LC stabilizers from five distinct chemotypes. We then obtained structural biological information on two classes of hits, coumarins and hydantoins, revealing that both chemotypes bind to a pocket at the V-V interface of the FL LC dimer. Here, we report crystal structures of three screening hits from two other chemotypes, diaryl hydrazones and sulfones, in complex with an amyloidogenic FL LC. While two of these hits bind to the previously identified pocket, one diaryl hydrazone binds to a different pocket bisected by the C symmetry axis of the dimer. These data further expand on the FL LC stabilizer-binding surface that could be used in design of more potent FL LC aggregation inhibitors.
通过小分子“动力学稳定剂”结合来稳定淀粉样免疫球蛋白轻链（LCs）正作为治疗轻链淀粉样变性的一种新方法在研发中。通过高通量筛选，我们之前从五种不同的化学类型中鉴定出16种全长（FL）LC稳定剂。然后我们获得了关于两类命中化合物香豆素和乙内酰脲的结构生物学信息，揭示这两种化学类型都结合到FL LC二聚体V-V界面的一个口袋中。在此，我们报告来自另外两种化学类型二芳基腙和砜的三个筛选命中化合物与淀粉样FL LC复合物的晶体结构。虽然其中两个命中化合物结合到先前鉴定的口袋，但一种二芳基腙结合到由二聚体C对称轴平分的另一个不同口袋。这些数据进一步扩展了FL LC稳定剂结合表面，可用于设计更有效的FL LC聚集抑制剂。
