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A facile approach to generate potent peptide inhibitors of the Zika virus protease
Patil, N. A., Quek, J.-P., Schroeder, B., Morewood, R., Rademann, J., Luo, D., & Nitsche, C. (2021). 2-Cyanoisonicotinamide conjugation: A facile approach to generate potent peptide inhibitors of the Zika virus protease. ACS Medicinal Chemistry Letters, 12(5), 732-737. https://doi.org/10.1021/acsmedchemlett.0c00657
The rapid generation and modification of macrocyclic peptides in medicinal chemistry is an ever-growing area that can cys present various synthetic challenges. The reaction between N-terminal cysteine and 2-cyanoisonicotinamide is a new biocompatible click reaction that allows rapid access to macrocyclic peptides. Importantly, 2-cyanoisonicotinamide can be attached to different linkers directly during solid-phase peptide synthesis. The synthesis involves only commercially available precursors, allowing for a fully automated process. We demonstrate the approach for four cyclic peptide ligands of the Zika virus protease NS2B-NS3. Although all peptides display the substrate recognition motif, the activity strongly depends on the linker length, with the shortest cyclization linker corresponding to highest activity (K-i = 0.64 mu M). The most active cyclic peptide displays affinity 78 times higher than that of its linear analogue. We solved a crystal structure of the proteolytically cleaved ligand and synthesized it by applying the presented chemistry to peptide ligation.
