Developing non-carbohydrate glycomimetics targeted to bacterial lectins

蛋白质-碳水化合物相互作用在许多生物过程的第一步中起着关键作用，例如免疫细胞的受精和组织归巢，但也在感染、炎症、肿瘤细胞的迁移和其他病理过程中起着关键作用。病原微生物（病毒、细菌、真菌和寄生虫）已经发展出利用人体组织上的聚糖表位进行特异性识别、粘附和细胞内化的策略。涉及的蛋白质可以是病毒衣壳结构域、菌毛顶部的粘附素、可溶性凝集素或酶或毒素的碳水化合物结合结构域。它们的碳水化合物结合位点对位于人类上皮细胞上的聚糖（如ABO和Lewis系统的组织/血型低聚糖）具有特异性。因此，能够干扰这种凝集素/聚糖相互作用的分子作为抗感染剂受到高度关注。类似地，人类凝集素也参与与炎症和癌症相关的慢性疾病，因此寻找凝集素抑制剂来干扰这些病理条件是非常有趣的。该项目旨在开发未开发的非碳水化合物类药物凝集素抑制剂领域。这种糖模拟物可以克服目前基于碳水化合物的治疗方法的局限性，如药代动力学和药效学限制以及合成的可追溯性。针对来自机会性细菌的三种凝集素，两个法国和两个德国实验室的联盟提出使用功能分析和核磁共振方法结合虚拟和体外化学文库筛选，然后进行结构（x射线，核磁共振），热力学（ITC）和动力学（SPR， MD）指导先导物优化。还将设想将铅结构组装成寡聚化合物，以便利用天然凝集素的多价性获得非常高的亲和力。本项目旨在建立一种广泛适用的方法来开发非碳水化合物凝集素抑制剂。选择了三种不同且具有代表性的细菌凝集素来探索发现管道的潜力。然而，这种方法并不局限于细菌靶点，其他具有高治疗意义的病毒、真菌或人凝集素也可以作为靶点。虽然管道开发是我们的主要关注点，但可以预见会产生新的抗感染药物（即解决问题的努力）。此外，这一努力将有助于我们对涉及多价受体的生物过程的基本理解，如膜动力学和脂质筏介导的内化（即好奇心驱动的研究）。

Protein-carbohydrate interactions play a key role in the first step of numerous biological processes, e.g. fertilization and tissue homing of immune cells, but also in infection, inflammation, migration of tumor cells and other pathologies. Pathogenic microorganisms (viruses, bacteria, fungi and parasites) have developed strategies for utilizing glycan epitopes on human tissues for specific recognition, for adhesion and sometimes for cellular internalization. The proteins involved can be viral capsid domains, adhesins on top of pili, soluble lectins or carbohydrate binding domains of enzymes or toxins. Their carbohydrate-binding sites are specific for glycans located on human epithelia such as the histo/blood group oligosaccharides of ABO and Lewis systems. Molecules that could interfere with such lectin/glycan interaction are therefore of high interest as anti-infectious agents. Similarly human lectins are involved in chronic diseases related to inflammation and cancer, and consequently the search for lectin inhibitors to interfere with these pathological conditions is of outstanding interest. The project aims at the development of the underexplored area of non-carbohydrate drug-like lectin inhibitors. Such glycomimetics could overcome current limitations of carbohydrate-based therapeutics such as pharmacokinetic and pharmacodynamic limitations as well as synthetic tractability. Targeting three lectins from opportunistic bacteria, the consortium of two French and two German laboratories proposes to combine virtual and in vitro screening of chemical libraries using functional assays and NMR approaches, followed by structure (X-ray, NMR), thermodynamics (ITC) and kinetics (SPR, MD) guided lead optimization. Assembling of lead structures into oligomeric compounds in order to use natural lectin multivalency to gain very high affinity will be also envisaged. This project aims at the establishment of a broadly applicable methodology for the development of non-carbohydrate lectin inhibitors. A set of three diverse and representative bacterial lectins was chosen to explore the potential of the discovery pipeline. However, this approach will not be limited to bacterial targets and other viral, fungal, or human lectins of high therapeutic significance can be targeted as well. While pipeline development is our major concern, generating novel anti-infectives is foreseen (i.e. a problem-solving endeavor). Moreover, this endeavor will contribute to our fundamental understanding of biological processes involving multivalent receptors such as membrane dynamics and lipid raft-mediated internalization (i.e. a curiosity driven research).