以整合素为靶向的多肽免疫药物的高通量单分子研究

Integrins are transmembrane adhesion receptors that play vital roles in immune responses, and have been implicated in inflammation, thrombosis, and tumor cell proliferation, migration and survival. Integrins transmit signals of shear stress, stretching, and ligand-binding, through conformational changes bi-directionally into and out of the cell. The mechano-chemical coupling is a key subject of molecular and cellular mechanics. Though around 16 molecules targeting integrins have passed partial clinical trials, few has been widely prescribed due to consequent side effects. We find that previous screening processes have not clarified the conformations changes of integrins and their responses to force. Our collaborator at Harvard Medical School recent reports 3 types of ligands for potential drug development. We will use single molecule vertical magnetic tweezers, electronic microscopy, STORM, residue mutation, and physical modeling, to study the conformational responses of integrins to force and the 3 types of ligands. A bottleneck of single molecular force spectroscopy is its low throughput. We will develop high throughput magnetic tweezers for high-efficiency drug screening and discovery.

整合素是细胞跨膜粘附受体，与炎症、血栓、及肿瘤细胞的增殖、迁移和凋亡等密切相关，在免疫系统中有重要作用。整合素是一种信号转导分子，能对血流剪应力、拉力和配体作用做出响应，产生构象变化，并把信号传给细胞内或胞外的其他分子。这种力-化学耦合相互作用是分子和细胞力学的热点课题。发现和筛选能与整合素或其配体发生作用的小分子，是药物研发的重要方向。虽有16种分子已进入至少临床试验I期，但使用后都出现一些问题。我们发现以往药物筛选时没有查明整合素构象变化，也缺少力学测试。近期我们在哈佛的合作方发现了3类有药用潜力的配体。我们将采用单分子纵向磁镊、电镜、超分辨率单分子成像、定点突变、模拟计算等方法技术，精确测定力和3种配体引起的整合素αVβ6和αIIbβ3的构象变化。单分子力谱一次只能测一个分子、效率有待提高。我们将发展高通量单分子磁镊技术，提高检测和筛选效率，推进有关药物的研发。

整合素是细胞跨膜粘附受体，与炎症、血栓、及肿瘤细胞的增殖、迁移和凋亡等密切相关，在免疫系统中有重要作用。整合素是一种信号转导分子，能对血流剪应力、拉力和配体作用做出响应，产生构象变化，并把信号传给细胞内或胞外的其他分子。这种力-化学偶合相互作用是分子和细胞力学的重要课题。发现和筛选能与整合素或其配体发生作用的小分子，是药物研发的重要方向。虽有16种分子已进入至少临床试验I期，但使用后都出现一些问题。我们发现以往药物筛选时没有查明整合素构象变化，也缺少力学测试。近期我们在哈佛的合作方发现了3类有药用潜力的配体。我们将采用单分子纵向磁镊、电镜、超分辨率单分子成像、定点突变、模型计算等方法技术，精确测定力和3种配体引起的整合素αVβ6的构象变化。单分子力谱一次只能测一个分子、效率有待提高。我们将发展高通量单分子磁镊技术，提高检测和筛选效率，推进有关药物的研发。