Gestwicki Jason E, Cairo Christopher W, Strong Laura E, Oetjen Karolyn A, Kiessling Laura L
Departments of Biochemistry and Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
J Am Chem Soc. 2002 Dec 18;124(50):14922-33. doi: 10.1021/ja027184x.
Multivalent ligands can function as inhibitors or effectors of biological processes. Potent inhibitory activity can arise from the high functional affinities of multivalent ligand-receptor interactions. Effector functions, however, are influenced not only by apparent affinities but also by alternate factors, including the ability of a ligand to cluster receptors. Little is known about the molecular features of a multivalent ligand that determine whether it will function as an inhibitor or effector. We envisioned that, by altering multivalent ligand architecture, ligands with preferences for different binding mechanisms would be generated. To this end, a series of 28 ligands possessing structural diversity was synthesized. This series provides the means to explore the effects of ligand architecture on the inhibition and clustering of a model protein, the lectin concanavalin A (Con A). The structural parameters that were varied include scaffold shape, size, valency, and density of binding elements. We found that ligands with certain architectures are effective inhibitors, but others mediate receptor clustering. Specifically, high molecular weight, polydisperse polyvalent ligands are effective inhibitors of Con A binding, whereas linear oligomeric ligands generated by the ring-opening metathesis polymerization have structural properties that favor clustering. The shape of a multivalent ligand also influences specific aspects of receptor clustering. These include the rate at which the receptor is clustered, the number of receptors in the clusters, and the average interreceptor distance. Our results indicate that the architecture of a multivalent ligand is a key parameter in determining its activity as an inhibitor or effector. Diversity-oriented syntheses of multivalent ligands coupled with effective assays that can be used to compare the contributions of different binding parameters may afford ligands that function by specific mechanisms.
多价配体可作为生物过程的抑制剂或效应器发挥作用。多价配体 - 受体相互作用的高功能亲和力可产生强大的抑制活性。然而，效应器功能不仅受表观亲和力影响，还受其他因素影响，包括配体使受体聚集的能力。关于决定多价配体是作为抑制剂还是效应器发挥作用的分子特征，人们知之甚少。我们设想，通过改变多价配体结构，可生成对不同结合机制有偏好的配体。为此，合成了一系列具有结构多样性的28种配体。该系列提供了探索配体结构对模型蛋白伴刀豆球蛋白A（Con A）抑制和聚集作用影响的方法。变化的结构参数包括支架形状、大小、价态和结合元件密度。我们发现，具有某些结构的配体是有效的抑制剂，而其他配体介导受体聚集。具体而言，高分子量、多分散的多价配体是Con A结合的有效抑制剂，而通过开环易位聚合产生的线性寡聚配体具有有利于聚集的结构特性。多价配体的形状也影响受体聚集的特定方面。这些方面包括受体聚集的速率、聚集体中受体的数量以及受体间的平均距离。我们的结果表明，多价配体的结构是决定其作为抑制剂或效应器活性的关键参数。多价配体的多样性导向合成与可用于比较不同结合参数贡献的有效测定方法相结合，可能会提供通过特定机制发挥作用的配体。
