Two-Component Stapling of Biologically Active and Conformationally Constrained Peptides: Past, Present, and Future
Two-Component Stapling of Biologically Active and Conformationally Constrained Peptides: Past, Present, and Future
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DOI：
10.1002/adtp.201800052
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发表时间：
2018-11-01
影响因子：
4.6
通讯作者：
Spring, David R.
中科院分区：
文献类型：
--
作者：
Iegre, Jessica;Gaynord, Josephine S.;Spring, David R.
肽是制药界新兴的一类治疗药物。虽然小分子在治疗领域占据主导地位数十年，但肽药物的设计和应用正在制药行业和学术界兴起。尽管肽具有高度选择性和有效性，但其药代动力学特性较差，其生物利用度的改善仍然是一个主要障碍。在肽中加入构象限制（例如肽装订）已被广泛用于提高这些分子的生物利用度；因此，开发了大量的缝合技术并对肽疗法的发展产生了重大影响也就不足为奇了。在众多已知的装订技术中，双组分方法允许肽的轻松且不同的功能化。作者首创了一种钉合技术，该技术利用二叠氮肽和功能化二炔基钉之间的双铜催化叠氮-炔环加成。近年来，作者创建了具有生物活性、构象受限的肽，用细胞穿透肽、荧光标签和光交联部分进行功能化，证明了该方法的广泛适用性。本文重点介绍了该技术和其他二组分肽装订技术对临床相关肽开发的影响、优势、局限性和未来应用。
Peptides are an emerging class of therapeutics in the pharmaceutical world. Whilst small molecules have dominated the therapeutic landscape for decades, the design and application of peptide drugs is emerging among the pharmaceutical industries and academia. Although highly selective and efficacious, peptides are characterized by poor pharmacokinetic properties and amelioration of their bioavailability remains a major hurdle. Incorporation of conformational constraints within the peptide (such as peptide stapling) has been extensively used to improve the bioavailability of these molecules; consequently, it is not surprising that a plethora of stapling techniques has been developed and has had a significant impact on the development of peptide therapeutics. Among the numerous stapling techniques known, two-component methodologies allow facile and divergent functionalization of peptides. The authors have pioneered a stapling technique that makes use of the double Cu-catalyzed azide-alkyne cycloaddition between di-azido peptides and functionalized di-alkynyl staples. In recent years, the authors have created biologically active, conformationally constrained peptides functionalized with cell-penetrating peptides, fluorescent tags, and photo cross-linking moieties, demonstrating the wide applicability of this methodology. Herein, the impact, advantages, limitations, and future applications of this technology and other two-component peptide stapling techniques on the development of clinically relevant peptides are highlighted.