Hartweg Manuel, Jiang Yivan, Yilmaz Gokhan, Jarvis Cassie M, Nguyen Hung V-T, Primo Gastón A, Monaco Alessandra, Beyer Valentin P, Chen Kathleen K, Mohapatra Somesh, Axelrod Simon, Gómez-Bombarelli Rafael, Kiessling Laura L, Becer C Remzi, Johnson Jeremiah A
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
JACS Au. 2021 Aug 10;1(10):1621-1630. doi: 10.1021/jacsau.1c00255. eCollection 2021 Oct 25.
Carbohydrate-binding proteins (lectins) play vital roles in cell recognition and signaling, including pathogen binding and innate immunity. Thus, targeting lectins, especially those on the surface of immune cells, could advance immunology and drug discovery. Lectins are typically oligomeric; therefore, many of the most potent ligands are multivalent. An effective strategy for lectin targeting is to display multiple copies of a single glycan epitope on a polymer backbone; however, a drawback to such multivalent ligands is they cannot distinguish between lectins that share monosaccharide binding selectivity (e.g., mannose-binding lectins) as they often lack molecular precision. Here, we describe the development of an iterative exponential growth (IEG) synthetic strategy that enables facile access to synthetic glycomacromolecules with precisely defined and tunable sizes up to 22.5 kDa, compositions, topologies, and absolute configurations. Twelve discrete mannosylated "glyco-IEGmers" are synthesized and screened for binding to a panel of mannoside-binding immune lectins (DC-SIGN, DC-SIGNR, MBL, SP-D, langerin, dectin-2, mincle, and DEC-205). In many cases, the glyco-IEGmers had distinct length, stereochemistry, and topology-dependent lectin-binding preferences. To understand these differences, we used molecular dynamics and density functional theory simulations of octameric glyco-IEGmers, which revealed dramatic effects of glyco-IEGmer stereochemistry and topology on solution structure and reveal an interplay between conformational diversity and chiral recognition in selective lectin binding. Ligand function also could be controlled by chemical substitution: by tuning the side chains of glyco-IEGmers that bind DC-SIGN, we could alter their cellular trafficking through alteration of their aggregation state. These results highlight the power of precision synthetic oligomer/polymer synthesis for selective biological targeting, motivating the development of next-generation glycomacromolecules tailored for specific immunological or other therapeutic applications.
碳水化合物结合蛋白（凝集素）在细胞识别和信号传导中发挥着至关重要的作用，包括病原体结合和固有免疫。因此，靶向凝集素，尤其是免疫细胞表面的凝集素，可能会推动免疫学和药物发现的发展。凝集素通常是寡聚体；因此，许多最有效的配体是多价的。凝集素靶向的一种有效策略是在聚合物主链上展示单个聚糖表位的多个拷贝；然而，这种多价配体的一个缺点是，由于它们通常缺乏分子精确性，无法区分具有相同单糖结合选择性的凝集素（例如，甘露糖结合凝集素）。在这里，我们描述了一种迭代指数增长（IEG）合成策略的开发，该策略能够轻松获得尺寸精确界定且可调、最大可达22.5 kDa、具有特定组成、拓扑结构和绝对构型的合成糖大分子。我们合成了12种离散的甘露糖化“糖-IEGmers”，并筛选它们与一组甘露糖苷结合免疫凝集素（DC-SIGN、DC-SIGNR、MBL、SP-D、朗格汉斯蛋白、dectin-2、小胶质细胞激发受体、DEC-205）的结合情况。在许多情况下，糖-IEGmers具有独特的长度、立体化学和拓扑结构依赖性凝集素结合偏好。为了理解这些差异，我们对八聚体糖-IEGmers进行了分子动力学和密度泛函理论模拟，结果揭示了糖-IEGmer立体化学和拓扑结构对溶液结构的显著影响，并揭示了选择性凝集素结合中构象多样性和手性识别之间的相互作用。配体功能也可以通过化学取代来控制：通过调节与DC-SIGN结合的糖-IEGmers的侧链，我们可以通过改变它们的聚集状态来改变它们在细胞内的运输。这些结果突出了精确合成寡聚物/聚合物合成在选择性生物靶向方面的强大作用，推动了为特定免疫学或其他治疗应用量身定制的下一代糖大分子的开发。
