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Multicomponent Reactions in Ligation and Bioconjugation Chemistry
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2018-05-25 00:00:00 , DOI: 10.1021/acs.accounts.8b00126
Leslie Reguera 1 , Yanira Méndez 1 , Ana R. Humpierre 1 , Oscar Valdés 2 , Daniel G. Rivera 1
Affiliation  

Multicomponent reactions (MCRs) encompass an exciting class of chemical transformations that have proven success in almost all fields of synthetic organic chemistry. These convergent procedures incorporate three or more reactants into a final product in one pot, thus combining high levels of complexity and diversity generation with low synthetic cost. Striking applications of these processes are found in heterocycle, peptidomimetic, and natural product syntheses. However, their potential in the preparation of large macro- and biomolecular constructs has been realized just recently. This Account describes the most relevant results of our group in the utilization of MCRs for ligation/conjugation of biomolecules along with significant contributions from other laboratories that validate the utility of this special class of bioconjugation process. Thus, MCRs have proven to be efficient in the ligation of lipids to peptides and oligosaccharides as well as the ligation of steroids, carbohydrates, and fluorescent and affinity tags to peptides and proteins. In the field of glycolipids, we highlight the power of isocyanide-based MCRs with the one-pot double lipidation of glycan fragments functionalized as either the carboxylic acid or amine. In peptide chemistry, the versatility of the multicomponent ligation strategy is demonstrated in both solution-phase lipidation protocols and solid-phase procedures enabling the simultaneous lipidation and biotinylation of peptides. In addition, we show that MCRs are powerful methods for synchronized lipidation/labeling and macrocyclization of peptides, thus accomplishing in one step what usually requires long sequences. In the realm of protein bioconjugation, MCRs have also proven to be effective in labeling, site-selective modification, immobilization, and glycoconjugation processes. For example, we illustrate a successful application of multicomponent polysaccharide–protein conjugation with the preparation of multivalent glycoconjugate vaccine candidates by the ligation of two antigenic capsular polysaccharides of a pathogenic bacterium to carrier proteins. By highlighting the ability to join several biomolecules in only one synthetic operation, we hope to encourage the biomolecular chemistry community to apply this powerful chemistry to novel biomedicinal challenges.

中文翻译:

连接和生物共轭化学中的多组分反应

多组分反应(MCR)涵盖了令人兴奋的一类化学转化,在合成有机化学的几乎所有领域中都已证明是成功的。这些收敛程序将三种或更多种反应物合并到一个罐中的最终产品中,从而将高水平的复杂性和多样性的产生与较低的合成成本相结合。在杂环,拟肽和天然产物合成中发现了这些方法的惊人应用。然而,它们在制备大分子和生物分子构建体中的潜力是最近才意识到的。该说明描述了我们小组在利用MCR进行生物分子的连接/偶联中最相关的结果,以及其他实验室的大量贡献,这些结果证实了这一特殊类别的生物偶联过程的实用性。因此,已经证明,MCR在脂质与肽和寡糖的连接以及类固醇,碳水化合物以及荧光和亲和标签与肽和蛋白质的连接中是有效的。在糖脂领域,我们着重介绍了基于异氰化物的MCR的功能,即一键式加成功能化为羧酸或胺的聚糖片段的双重脂化作用。在肽化学中,多组分连接策略的多功能性已在溶液相脂质化方案和固相程序中得到证实,从而可以同时进行肽脂质化和生物素化。此外,我们表明,MCR是同步脂化/标记和多肽大环化的强大方法,因此只需一步即可完成通常需要长序列的操作。在蛋白质生物结合领域,还已经证明,MCR在标记,位点选择性修饰,固定化和糖缀合过程中有效。例如,我们通过将致病细菌的两个抗原荚膜多糖与载体蛋白连接,证明了多组分多糖-蛋白结合与多价糖缀合物疫苗候选物制备的成功应用。通过强调仅在一个合成操作中就能结合几种生物分子的能力,我们希望鼓励生物分子化学界将这种强大的化学方法应用于新的生物医学挑战。我们通过病原菌的两个抗原荚膜多糖与载体蛋白的连接,说明了多组分多糖-蛋白结合与多价糖缀合物疫苗候选物制备的成功应用。通过强调仅在一个合成操作中就能结合几种生物分子的能力,我们希望鼓励生物分子化学界将这种强大的化学方法应用于新的生物医学挑战。我们通过病原菌的两个抗原荚膜多糖与载体蛋白的连接,说明了多组分多糖-蛋白结合与多价糖缀合物疫苗候选物制备的成功应用。通过强调仅在一个合成操作中就能结合几种生物分子的能力,我们希望鼓励生物分子化学界将这种强大的化学方法应用于新的生物医学挑战。
更新日期:2018-05-25
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