2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease

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 macrocycli...

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Main Authors: Patil, Nitin A., Quek, Jun-Ping, Schroeder, Barbara, Morewood, Richard, Rademann, Jörg, Luo, Dahai, Nitsche, Christoph
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/149908
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1499082023-03-05T16:49:46Z 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease Patil, Nitin A. Quek, Jun-Ping Schroeder, Barbara Morewood, Richard Rademann, Jörg Luo, Dahai Nitsche, Christoph Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Macrocyclization Peptides 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. National Research Foundation (NRF) Accepted version N.A.P thanks the National Health and Medical Research Council, Australia for the Peter Doherty Early Career Research Fellowship (APP1158171). J.-P.Q. is supported by the Nanyang Presidential Graduate Scholarship. B.S. acknowledges a travel fellowship from the Ernst-Reuter-Gesellschaft and Research Alumni program, Berlin, Germany. J.R. is grateful for a visiting fellowship of the Australian National University. D.L. acknowledges the support from Singapore National Research Foundation Grant NRF2016NRF-CRP001-063. C.N. thanks the Australian Research Council for a Discovery Early Career Research Award (DE190100015). 2021-05-25T02:47:19Z 2021-05-25T02:47:19Z 2021 Journal Article 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 1948-5875 0000-0003-0422-9411 0000-0001-6678-3165 0000-0002-3704-2699 https://hdl.handle.net/10356/149908 10.1021/acsmedchemlett.0c00657 2-s2.0-85104909759 5 12 732 737 en NRF2016NRF-CRP001-063 ACS Medicinal Chemistry Letters 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 application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Macrocyclization
Peptides
spellingShingle Science::Medicine
Macrocyclization
Peptides
Patil, Nitin A.
Quek, Jun-Ping
Schroeder, Barbara
Morewood, Richard
Rademann, Jörg
Luo, Dahai
Nitsche, Christoph
2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
description 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Patil, Nitin A.
Quek, Jun-Ping
Schroeder, Barbara
Morewood, Richard
Rademann, Jörg
Luo, Dahai
Nitsche, Christoph
format Article
author Patil, Nitin A.
Quek, Jun-Ping
Schroeder, Barbara
Morewood, Richard
Rademann, Jörg
Luo, Dahai
Nitsche, Christoph
author_sort Patil, Nitin A.
title 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
title_short 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
title_full 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
title_fullStr 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
title_full_unstemmed 2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease
title_sort 2-cyanoisonicotinamide conjugation: a facile approach to generate potent peptide inhibitors of the zika virus protease
publishDate 2021
url https://hdl.handle.net/10356/149908
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