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Continue to Iris Biotech GmbHSend request to US distributorPublished on 15/01/2025
In contrast to the original CuAAC click reaction, strain-promoted azide-alkyne cycloaddition (SPAAC, 2nd generation click chemistry) has the advantage that no heavy metals (copper or ruthenium ions) are required, which otherwise would need to be carefully removed before applying the reaction product to biological systems. Also, copper-based click chemistry cannot be used when metal-chelating ligands like DOTA are present, as in the case of, e.g., radiotheranostics.
In the copper-free 2nd generation click chemistry, strained alkynes are used. The reactivity of the alkyne strongly depends on the strain of the triple bond in a cyclic system, which is mostly determined by the substituents of the ring. This variety of click reactions is also referred to as strain-promoted azide-alkyne click chemistry (SPAAC).
Here, CliCr® comes into play: CliCr® (tetramethyl-thioheptynesulfoximine, TMTHSI) is an innovative strained cyclic alkyne with ideal properties for metal-free strain-promoted click chemistry: It shows high solubility in aqueous solvents and fast kinetics at ambient temperature. Other key benefits are its small size and broad compatibility. CliCr® is a versatile platform that can be applied to virtually any bioconjugation reaction. It has been successfully used with small molecules, nanoparticles, peptides, proteins, and siRNA.
This plot illustrates the low hydrophobicity and high reactivity of TMTHSI (CliCr®, upper left corner) in contrast to other commonly used alkynes for strain-promoted azide-alkyne cycloaddition (SPAAC).
The 7-membered CliCr® ring may be functionalized as needed with amino-reactive reagents, e.g., by acylation, sulfonylation, N-alkylation, or carbamoylation. Hence, CliCr® may be used in diverse applications, e.g., for the construction of antibody-drug conjugates (ADCs), for ex vivo cell modification (e.g., CAR-T), for small molecule-drug conjugates, for oligonucleotide conjugates (including with trigger sensitive release) as well as for diagnostic labelling of a variety of agents. CliCr® handles may be introduced site-specifically during solid phase peptide synthesis (SPPS), as TMTHS is uniquely stable against the harsh (acidic) cleavage conditions commonly used in SPPS.
In addition to the CliCr® base compound (RL-4200), three off-the-shelf TMTHSI-derivatives are available: amino functionalized with beta-alanine (RL-4190), carboxy functionalized with succinic acid (RL-4200), and amino-reactive as succinimide activated ester (RL-4330). Others, including a 2PCA derivative for N-terminus specific conjugation, can custom specific be generated. To help maximize your results with CliCr®, you can benefit from a CliCr® feasibility service package (RL-4205) comprising 20 hours of consulting and advice by experts of Cristal Therapeutics for the period of 1 year.
In the following, we’ll address some frequently asked questions on CliCr®:
· What are typical conversion efficiencies using CliCr®?
Depending on the application and conditions, generally high (more than 90%) conversions can be achieved with a slight excess of 1.1 equivalents of CliCr® to 1 equivalent of azide, making CliCr® very cost-efficient.
· What are standard purification strategies?
Straightforward purification of small molecules, peptides, siRNA, proteins, and nanoparticles have been demonstrated. In case of large size differences between the reagents and the product, spin filtration, tangential flow filtration or gel filtration (e.g., with PD10 columns) have removed over 99% of the unreacted CliCr® reagent. For smaller size differences, beads with immobilized azides are very efficient as a purification tool.
· What are typical analysis methods to characterize a CliCr® reagent and/or remaining unreacted material?
This depends on the specific application. HPLC-UV/MS works well for smaller conjugates. NMR can provide quantitative insight into larger conjugates (e.g., via 15N NMR for the triazole formation in polymers).
· What (storage) conditions should be avoided with CliCr® reagents?
Prolonged storage in alcohols (MeOH, EtOH, i-PrOH) may cause the partial reduction of the triple bond. Exposure to strong HCl can lead to the addition of HCl to the triple bond. This may also undergo a Diels-Alder reaction with certain dienes.
· What is the maximum production scale of CliCr®?
Currently, CliCr® as base compound is available in quantities up to 100 grams.
· Is there already GMP grade material available?
The production process is fully GMP-compatible, and ready for GMP batch production.
→ You need more details? Watch the recording of our webinar!
→ Discover our portfolio of azide derivatives!
→ For any questions and inquiries, feel free to get in contact!
References:
TMTHSI, a superior 7-membered ring alkyne containing reagent for strain-promoted azide–alkyne cycloaddition reactions; J. Weterings, C. J. F. Rijcken, H. Veldhuis, T. Meulemans, D. Hadavi, M. Timmers, M. Honing, H. Ippeld, R. M. J. Liskamp; Chem. Sci. 2020; 11(33): 9011-9016. https://doi.org/10.1039/D0SC03477K
Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide–Alkyne Cycloaddition Reactions; M. Timmers, A. Kipper, R. Frey, S. Notermans, M. Voievudskyi, C. Wilson, N. Hentzen, M. Ringle, C. Bovino, B. Stump, C. J. F. Rijcken, T. Vermonden, I. Dijkgraaf, R. Liskamp; Pharmaceuticals (Basel) 2023; 16(8): 1155-1169. https://doi.org/10.3390/ph16081155
Specific N-terminal attachment of TMTHSI linkers to native peptides and proteins for strain-promoted azide alkyne cycloaddition; M. Timmers, W. Peeters, N. J Hauwert, C. J. F. Rijcken, T. Vermonden, I. Dijkgraaf, R. M. J. Liskamp; Chem. Commun. (Camb) 2023; 59(76): 11397-11400. https://doi.org/10.1039/d3cc03397j
Versatile Click Linker Enabling Native Peptide Release from Nanocarriers upon Redox Trigger; E. R. Hebels, S. Dietl, M. Timmers, J. Hak, A. van den Dikkenberg, C. J. F. Rijcken, W. E. Hennink, R. M. J. Liskamp, T. Vermonden; Bioconj. Chem. 2023; 34(12): 2375-2386. https://doi.org/10.1021/acs.bioconjchem.3c00484
One-step; site-specific modification of native proteins with 2-pyridinecarboxyaldehydes; J. I. MacDonald, H. K. Munch, T. Moore and M. B. Francis; Nat. Chem. Biol. 2015, 11(5): 326–331. https://doi.org/10.1038/nchembio.1792
Selective N-terminal modification of peptides and proteins: Recent progresses and applications; H. Jiang, W. Chen, J. Wang, R. Zhang; Chin Chem. Lett. 2022; 33(1): 80-88. https://doi.org/10.1016/j.cclet.2021.06.011
An N terminomics toolbox combining 2-pyridinecarboxaldehyde probes and click chemistry for profiling protease specificity; H. N. Bridge, W. Leiter, C. L. Frazier, A. M. Weeks; Cell Chem. Biol. 2024; 31(3): 534-549. https://doi.org/10.1016/j.chembiol.2023.09.009