Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/149908
Title: 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
Authors: Patil, Nitin A.
Quek, Jun-Ping
Schroeder, Barbara
Morewood, Richard
Rademann, Jörg
Luo, Dahai
Nitsche, Christoph
Keywords: Science::Medicine
Issue Date: 2021
Source: Patil, N. A., Quek, J., 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://dx.doi.org/10.1021/acsmedchemlett.0c00657
Project: NRF2016NRF-CRP001-063
Journal: ACS Medicinal Chemistry Letters
Abstract: The rapid generation and modification of macrocyclic peptides in medicinal chemistry is an ever-growing area that can 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 (Ki = 0.64 μM). 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.
URI: https://hdl.handle.net/10356/149908
ISSN: 1948-5875
DOI: 10.1021/acsmedchemlett.0c00657
Rights: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsmedchemlett.0c00657
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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