Abstract
Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.
Highlights
Peptide-based drugs are becoming an important component of the pharmaceutical drug market, especially since new techniques have been developed in recent years to improve production, reduce metabolic breakdown, and introduce alternative routes of administration
We focus on the application of CuAAC click chemistry in peptide-based drug discovery (Figure 1)
Co-crystal structures with human immunodeficiency virus type-1 (HIV-1) protease showed that inhibitors were bound in a position identical to that of parent compound amprenavir (1, Figure 2), arguing that the triazole was functioning as an excellent mimic of the peptide bond group in this class of molecules
Summary
Peptide-based drugs are becoming an important component of the pharmaceutical drug market, especially since new techniques have been developed in recent years to improve production, reduce metabolic breakdown, and introduce alternative routes of administration. Cu(I) catalyzed [3+2] cycloaddition reaction, often referred to as “click chemistry”, was conceived by Sharpless et al and Meldal and colleagues [4,5] and has greatly enhanced access to chemical space of peptide-based components Some other reactions, such as thio-ene click reaction and Diels-Alder reaction, are considered as click chemistry. Sharpless and Fokin demonstrated that copper-catalyzed azide-alkyne cycloaddition (CuAAC) can be successfully performed in polar media such as t-butyl alcohol, ethanol or pure water [8] These findings led to a remarkable escalation in use of Huisgen cycloadditions, and, within the last few years, CuAAC has been exponentially investigated in organic synthesis, inorganic chemistry, polymer chemistry and biochemistry [9,10,11,12,13]. The replacement of unstable bonds with non-natural stable structures, while at the same time maintaining biological activity, can be useful for improving the drugability of peptides
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