Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química , 26006 Logroño, Spain.
Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Bijvoet Center for Biomolecular Research, Utrecht University , Universiteitsweg 99, Utrecht, The Netherlands.
J Am Chem Soc. 2017 Dec 20;139(50):18255-18261. doi: 10.1021/jacs.7b09447. Epub 2017 Dec 12.
A structure-based design of a new generation of tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-l-proline or 4,4-difluoro-l-proline, at the most immunogenic domain. Binding assays using biolayer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen-antibody complex by enhancing key CH/π interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for prostate cancer.
描述了一种基于结构的新一代肿瘤相关糖肽的设计，其对两种抗 MUC1 抗体的亲和力得到了改善。这些独特的抗原在最具免疫原性的结构域中具有一个氟化脯氨酸残基，如（4S）-4-氟-L-脯氨酸或 4,4-二氟-L-脯氨酸。使用生物层干涉测量法进行的结合测定显示，与天然（糖）肽相比，亲和力提高了 3 倍至 10 倍。根据 X 射线晶体学和 MD 模拟，氟化残基通过增强关键的 CH/π 相互作用稳定抗原-抗体复合物。有趣的是，用非天然抗原可以显著提高从前列腺癌患者血清中检测到的癌症相关抗 MUC1 抗体的水平，这证明与天然抗原相比，这些衍生物可以被认为是更好的前列腺癌诊断工具。
