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.This work was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC
grant agreement no. [279337/DOS] (to DRS) and the Wellcome Trust Strategic (090340/Z/09/Z)Award (to DRS and MH).
Engineering and Physical Sciences Research Council,
Biotechnology and Biological Sciences Research Council,
Medical Research Council
Royal Society
