Galecto Biotech AB, Sahlgrenska Science Park, Medicinaregatan 8A, 413 46, Gothenburg, Sweden.
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00, Lund, Sweden.
ChemMedChem. 2018 Jan 22;13(2):133-137. doi: 10.1002/cmdc.201700744. Epub 2018 Jan 15.
The design of small and high-affinity lectin inhibitors remains a major challenge because the natural ligand binding sites of lectin are often shallow and have polar character. Herein we report that derivatizing galactose with un-natural structural elements that form multiple non-natural lectin-ligand interactions (orthogonal multipolar fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond) can provide inhibitors with extraordinary affinity (low nanomolar) for the model lectin, galectin-3, which is more than five orders of magnitude higher than the parent galactose; moreover, is selective over other galectins.
设计小而高亲和力的凝集素抑制剂仍然是一个主要的挑战，因为凝集素的天然配体结合位点通常较浅且具有极性。在此，我们报告称，通过用非天然结构元素对半乳糖进行衍生化，可以形成多种非天然的凝集素-配体相互作用（正交多极氟酰胺、苯丙氨酸-精氨酸、硫-π 和卤键），从而为模型凝集素半乳凝集素-3 提供具有非凡亲和力（低纳摩尔）的抑制剂，其亲和力比母体半乳糖高五个数量级以上；此外，它对半乳糖凝集素具有选择性。
