Histidine Focused Covalent Library

For a long time, irreversible covalent inhibitors have been in the shadows of medicinal chemistry and drug discovery efforts due to their potential toxicity and related safety concerns. However, the approval of 8 covalent drugs over the past decade has restarted the active investigation for new targeted covalent inhibitors (TCIs). One of the main directions of the modern covalent inhibition research in drug development is focused on less studied amino acids (e.g. His, Arg, Met) and their potential to react with the new generation of TCIs irreversibly or reversibly [1].

Side-selective modification of histidine residue remains one of the most difficult and interesting challenges in covalent drug discovery due to its unique imidazole side chain. The nucleophilic heteroaromatic ring is mainly modified by the attack of the electrophiles and different N-substitutional reactions. Nonetheless, this approach remains vulnerable due to the possible covalent binding to serine and cysteine amino acid residues instead [2]. Therefore, the variety of chemoselective covalent modifiers for the histidine amino acid moiety is limited, covering the following structural moieties as potential covalent warheads: 2-cyclohexenone derivatives, and alkyl halides (chlorine derivatives are preferred), sulfonyl fluorides, α-сyanoenones, epoxides, and promising spiro-epoxides [3-7].

The Life Chemicals proprietary Histidine-focused Screening Compound Library comprises over 5,500 covalently binding molecules containing specific structure moieties that could react reversibly or irreversibly (by forming covalent bonds) with histidine residues of a drug target for efficient covalent screening. These small-molecule screening compounds are potential histidine-specific covalent inhibitors, selected from the Life Chemicals HTS Compound Collection based on the 13 most interesting covalent warheads that were reported in several articles [3-10]. They are split, herein, into a number of classes for convenient and quick search:

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Figure 1. Covalent warheads distribution for compounds in the Histidine-focused Covalent Inhibitor Library 

References

1. Sutanto F., Konstantinidou M., Dömling A. (2020) Covalent inhibitors: a rational approach to drug discovery. RSC Med Chem.;11(8):876-884. DOI: 10.1039/d0md00154f.
2. Brosnan M., Brosnan J. (2020) Histidine Metabolism and Function, The Journal of Nutrition, Volume 150, Issue Supplement_1, P 2570S-2575S, https://doi.org/10.1093/jn/nxaa079.
3. Joshi, P. N., & Rai, V. (2018). Single-site labeling of histidine in proteins, on-demand reversibility, and traceless metal-free protein purification. Chemical Communications. doi:10.1039/c8cc08733d.
4. Sornay, Ch., Vaur, V., Wagner, A. (2022) An overview of chemo- and site-selectivity aspects in the chemical conjugation of proteins. Soc. open sci. 9211563211563. http://doi.org/10.1098/rsos.211563.
5. Jia, S., He, D., & Chang, C. J. (2019). Bioinspired Thiophosphorodichloridate Reagents for Chemoselective Histidine Bioconjugation. Journal of the American Chemical Society. doi:10.1021/jacs.8b11912.
6. Narayanan, A., & Jones, L. H. (2015). Sulfonyl fluorides as privileged warheads in chemical biology. Chemical science, 6(5), 2650–2659. https://doi.org/10.1039/c5sc00408j.
7. Gehringer, M., & Laufer, S. A. (2018). Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology. Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.8b01153.
8. Adusumalli, S. R., Rawale, D. G., Singh, U. (2018). Single-site labeling of native proteins enabled by a chemoselective and site-selective chemical technology. Journal of the American Chemical Society. doi:10.1021/jacs.8b10490.
9. Powers, J. C., Asgian, J. L., Ekici, Ö. D., & James, K. E. (2002). Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases. Chemical Reviews, 102(12), 4639–4750. doi:10.1021/cr010182v.
10. Gehringer, M., & Laufer, S. A. (2018). Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology. Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.8b01153.
11. Ray, S., & Murkin, A. S. (2019). New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design. Biochemistry. doi:10.1021/acs.biochem.9b00293.
12. Benton, P. M. C., Mayer, S. M., Shao, J. (2001). Interaction of Acetylene and Cyanide with the Resting State of Nitrogenase α-96-Substituted MoFe Proteins. Biochemistry, 40(46), 13816–13825. doi:10.1021/bi011571m.