In situclick chemistry: from small molecule discovery to synthetic antibodies

Abstract

Advances in the fields of proteomics, molecular imaging, and therapeutics are closely linked to the availability of affinity reagents that selectively recognize their biological targets. Here we present a review of Iterative Peptide In Situ Click Chemistry (IPISC), a novel screening technology for designing peptide multiligands with high affinity and specificity. This technology builds upon in situ click chemistry, a kinetic target-guided synthesis approach where the protein target catalyzes the conjugation of two small molecules, typically through the azide–alkyne Huisgen cycloaddition. Integrating this methodology with solid phase peptide libraries enables the assembly of linear and branched peptide multiligands we refer to as Protein Catalyzed Capture Agents (PCC Agents). The resulting structures can be thought of as analogous to the antigen recognition site of antibodies and serve as antibody replacements in biochemical and cell-based applications. In this review, we discuss the recent progress in ligand design through IPISC and related approaches, focusing on the improvements in affinity and specificity as multiligands are assembled by target-catalyzed peptide conjugation. We compare the IPISC process to small molecule in situ click chemistry with particular emphasis on the advantages and technical challenges of constructing antibody-like PCC Agents.

From protein total synthesis to peptide transamidation and metathesis: playing with the reversibility of N,S-acyl or N,Se-acyl migration reactions

“…In this case, the reaction bringing the fragments together must be chemoselective and ideally irreversible. The Huisgen's cycloaddition reaction of azides with terminal alkynes [referred to as 'click' chemistry] has attracted a lot of attention in this field [3,4]. The second complementary strategy consists in producing a dynamic chemical library (DCL) which can adapt to the target present in the system (Figure 1c) [2 ].…”

Preparation of efficient magnetic biosorbents by clicking carbohydrates onto graphene oxide

“…Click chemistry [26] has seen broad implementation in polymer functionalization [27], surface modification [28], block copolymer and dendrimer synthesis [29], biomaterials fabrication [30], drugs [31], and in many other areas of materials science [32]. Click reaction was used as a facile strategy to attach saccharides onto dendrimers [33] and carbon nanotubes [34].…”

A new strategy for synthesis of branched cyclic peptide by Asn side-chain hydrazide ligation

“…A conventional approach is to incorporate a functionalized unnatural amino acid during peptide synthesis and the function group enables site-specific conjugation with another functionalized peptide. Several bioorthogonal reactions were applied in branched peptide synthesis, such as click chemistry with peptide azide and alkyne [10,11], native chemical ligation of peptide thioester and 4-mercapto-lysine [12], peptide hydrazide and aldehyde [13], etc.…”