Božinović Nina, Ajdačić Vladimir, Lazic Jelena, Lecerf Maxime, Daventure Victoria, Nikodinovic-Runic Jasmina, Opsenica Igor M, Dimitrov Jordan D
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, F-75006 Paris, France.
University of Belgrade-Faculty of Chemistry, Studentski trg 16, P.O. Box 51, 11158 Belgrade, Serbia.
ACS Omega. 2019 Nov 22;4(24):20450-20458. doi: 10.1021/acsomega.9b01548. eCollection 2019 Dec 10.
In a healthy immune repertoire, there exists a fraction of polyreactive antibodies that can bind to a variety of unrelated self- and foreign antigens. Apart from naturally polyreactive antibodies, in every healthy individual, there is a fraction of antibody that can gain polyreactivity upon exposure to porphyrin cofactor heme. Molecular mechanisms and biological significance of the appearance of cryptic polyreactivity are not well understood. It is believed that heme acts as an interfacial cofactor between the antibody and the newly recognized antigens. To further test this claim and gain insight into the types of interactions involved in heme binding, we herein investigated the influence of a group of aromatic guanylhydrazone molecules on the heme-induced antibody polyreactivity. From the analysis of SAR and the results of UV-vis absorbance spectroscopy, it was concluded that the most probable mechanism by which the studied molecules inhibit heme-mediated polyreactivity of the antibody is the direct binding to heme, thus preventing heme from binding to antibody and/or antigen. The inhibitory capacity of the most potent compounds was substantially higher than that of chloroquine, a well-known heme binder. Some of the guanylhydrazone molecules were able to induce polyreactivity of the studied antibody themselves, possibly by a mechanism similar to heme. Results described here point to the conclusion that heme indeed must bind to an antibody to induce its polyreactivity, and that both π-stacking interactions and iron coordination contribute to the binding affinity, while certain structures, such as guanylhydrazones, can interfere with these processes.
在健康的免疫库中，存在一部分多反应性抗体，它们能够结合多种不相关的自身和外来抗原。除了天然的多反应性抗体外，在每个健康个体中，都有一部分抗体在接触卟啉辅因子血红素后会获得多反应性。隐蔽多反应性出现的分子机制和生物学意义尚未完全了解。据信，血红素作为抗体与新识别抗原之间的界面辅因子。为了进一步验证这一说法并深入了解血红素结合所涉及的相互作用类型，我们在此研究了一组芳香胍腙分子对血红素诱导的抗体多反应性的影响。通过对构效关系的分析和紫外可见吸收光谱的结果，得出结论：所研究的分子抑制抗体血红素介导的多反应性的最可能机制是直接与血红素结合，从而阻止血红素与抗体和/或抗原结合。最有效化合物的抑制能力明显高于著名的血红素结合剂氯喹。一些胍腙分子自身能够诱导所研究抗体的多反应性，可能是通过与血红素类似的机制。这里描述的结果表明，血红素确实必须与抗体结合才能诱导其多反应性，并且π-堆积相互作用和铁配位都有助于结合亲和力，而某些结构，如胍腙，可能会干扰这些过程。
