当前位置: X-MOL 学术ChemMedChem › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Targeting the CRD F‐face of Human Galectin‐3 and Allosterically Modulating Glycan Binding by Angiostatic PTX008 and a Structurally Optimized Derivative
ChemMedChem ( IF 3.4 ) Pub Date : 2020-11-06 , DOI: 10.1002/cmdc.202000742
Michelle C Miller 1 , Yi Zheng 2 , Dennis Suylen 3 , Hans Ippel 3 , F Javier Cañada 4 , M Alvaro Berbís 4 , Jesús Jiménez-Barbero 4, 5, 6 , Guihua Tai 2 , Hans-Joachim Gabius 7 , Kevin H Mayo 1
Affiliation  

Calix[4]arene PTX008 is an angiostatic agent that inhibits tumor growth in mice by binding to galectin‐1, a β‐galactoside‐binding lectin. To assess the affinity profile of PTX008 for galectins, we used 15N,1H HSQC NMR spectroscopy to show that PTX008 also binds to galectin‐3 (Gal‐3), albeit more weakly. We identified the contact site for PTX008 on the F‐face of the Gal‐3 carbohydrate recognition domain. STD NMR revealed that the hydrophobic phenyl ring crown of the calixarene is the binding epitope. With this information, we performed molecular modeling of the complex to assist in improving the rather low affinity of PTX008 for Gal‐3. By removing the N‐dimethyl alkyl chain amide groups, we produced PTX013 whose reduced alkyl chain length and polar character led to an approximately eightfold stronger binding than PTX008. PTX013 also binds Gal‐1 more strongly than PTX008, whereas neither interacts strongly, if at all, with Gal‐7. In addition, PTX013, like PTX008, is an allosteric inhibitor of galectin binding to the canonical ligand lactose. This study broadens the scope for galectin targeting by calixarene‐based compounds and opens the perspective for selective galectin blocking.

中文翻译:

通过血管抑制 PTX008 和结构优化的衍生物靶向人半乳糖凝集素 3 的 CRD F 面和变构调节聚糖结合

Calix[4]arene PTX008 是一种血管抑制剂,通过与半乳糖凝集素 1(一种 β-半乳糖苷结合凝集素)结合来抑制小鼠的肿瘤生长。为了评估 PTX008 对半乳糖凝集素的亲和性,我们使用15 N, 1 H HSQC NMR 光谱显示 PTX008 也与半乳糖凝集素-3 (Gal-3) 结合,尽管更弱。我们在 Gal-3 碳水化合物识别域的 F 面上确定了 PTX008 的接触位点。STD NMR显示杯芳烃的疏水苯环冠是结合表位。有了这些信息,我们对复合物进行了分子建模,以帮助提高 PTX008 对 Gal-3 的相当低的亲和力。通过去除N‐二甲基烷基链酰胺基团,我们生产了 PTX013,其减少的烷基链长度和极性特征导致比 PTX008 强约八倍的结合。PTX013 与 Gal-1 的结合也比 PTX008 更强,而两者都与 Gal-7 相互作用强烈(如果有的话)。此外,与 PTX008 一样,PTX013 是半乳糖凝集素与经典配体乳糖结合的变构抑制剂。该研究拓宽了基于杯芳烃的化合物靶向半乳糖凝集素的范围,并为选择性阻断半乳糖凝集素开辟了前景。
更新日期:2020-11-06
down
wechat
bug