A common method for reliably and quickly producing complex compounds out of small parts is click chemistry. With this method, peptides and proteins can be modified by adding ligands, lipophilic or lipophobic groups, or hydrophilic or hydrophobic linkers, among other things. You may swiftly and effectively accomplish your click chemistry objectives with the aid of CPC.
|Click Peptide Services|
|Synthesis of clickable peptides containing alkyne or azide functionalities|
|Synthesis of clickable amino acids for incorporation into peptides|
|Synthesis of building blocks for peptide-click chemistry|
|Design and synthesis of substituted cyclooctyne-modified peptides for copper-free click reactions|
|Conjugation to small molecules, PEG chains, surfaces, metal-chelates, fluorophores, and sugars.|
|Bioconjugation, ligation, stapled peptides, and macrocyclization|
Chart 1. Cyclo[RGD-DPhe-Lys(Azido-PEG4)] (RDGP-011) is clickable peptide containing an azide moiety connected to a PEG4 linker and cyclic hexa RGD sequence that selectively binds to αvβ3 receptors on neovascular blood vessel sections of different major human cancers. RDGP-011 is available from stock from CPC Scientific.
A triazole link connecting two units is created by "clicking" an alkyne-modified peptide with an azide-modified molecule in the CuAAC click reactions (Figure 1). The click reaction is incredibly effective, broad in application, stereospecific, and easy to carry out with low-cost materials. Additionally, they have easy-to-isolate end products and can be carried out with benign solvents like water. The majority of click reactions involve carbon-heteroatom bonding mechanisms and have a high energy level that makes them irreversible. One of the most well-liked prototype click reactions to yet and one that forms a rigid five-membered triazole ring under mild circumstances is the copper-catalyzed azide-alkyne cycloaddition (CuAAC) between an alkyne and an azide. The azides have several functional properties that make them useful, including being simple to introduce, stable to water and oxidative conditions, orthogonal to many frequently used functional groups, and violently reactive. Azides are essentially absent from any naturally occurring species (bioorthogonal) for use in vitro and in vivo.
Figure 1. Click reaction between alkyne and azide peptide side chains.
Figure 2. Due to its relative planarity, strong dipole moment (~5 D), and hydrogen bonding ability, the 1, 2, 3-triazole function formed by a click reaction between an azide and alkyne bears a physicochemical resemblance to the amide bond.
Numerous peptide science applications have benefited from the versatility and dependability of CuAAC as well as the bioorthogonality of the initial reactants. The cyclization, chemical ligation, and conjugation to biomolecules, nanoparticles, polymers, and other chemical entities are some of the most significant uses of click chemistry in peptide research. There are numerous ways to modify peptides using click chemistry for a range of applications. For instance, post-synthesis can transform peptides into an azido derivative, which can then be clicked with the proper substrate that contains an alkynyl group, or vice versa. During peptide synthesis, amino acids or building blocks containing azide or alkyne can also be used to create peptides by inter- and intramolecular click reactions.
It is simple to synthesize triazole-stapled peptides because to the "click" reaction's high efficiency and benign conditions (Copper-catalyzed Huisgen 1,3-dipolar cycloaddition process) and the availability of the requisite unnatural amino acids (Figure 3). To make single triazole-stapled peptides, for instance, L-Nle (N3) and D-Pra (D-propargylalanine) can be combined and substituted at the i and i+4 locations, respectively.
Figure 4. Click chemistry provides an alternative to hydrocarbon stapling by way of triazole-stapled peptides.
Widespread in vivo uses of CuAAC click reactions are still constrained by copper's cytotoxicity, which is still a source of concern. The targeted biomolecules may degrade or aggregate in the presence of copper and/or reducing chemicals. Fortunately, employing copper-free "click" chemistry can solve these problems. This method is based on the interaction of cyclooctynes (such DIBAC and MOFO) with azides at room temperature without the use of a copper catalyst. The synthesis of a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide conjugate, made by attaching DOTA to monofluoro-cyclooctyne (MOFO) and then bioconjugating it with an azide-modified peptide, is a recent peptide application.
Figure 5. Copper-free click chemistry linkers: (1) monofluorinated cyclooctyne (MOFO), (2) dibenzoannulated cyclooctyne (DIBO), and (3) dibenzoazacyclooctyne (DIBAC).
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