7DOC

Crystal structure of Zika NS2B-NS3 protease with compound 5

Summary for 7DOC

• Entry DOI: 10.2210/pdb7doc/pdb
• Descriptor: Core protein, Genome polyprotein, Serine protease subunit NS2B, ... (9 entities in total)
• Functional Keywords: viral protease, protease inhibitor complex, viral protein
• Biological source: Zika virus (ZIKV); More
• Total number of polymer chains: 9
• Total formula weight: 83956.59

Authors

Quek, J.P. (deposition date: 2020-12-14, release date: 2021-04-14, Last modification date: 2024-07-10)

Primary citation

Patil, N.A.,Quek, J.P.,Schroeder, B.,Morewood, R.,Rademann, J.,Luo, D.,Nitsche, C.
2-Cyanoisonicotinamide Conjugation: A Facile Approach to Generate Potent Peptide Inhibitors of the Zika Virus Protease.
Acs Med.Chem.Lett., 12:732-737, 2021

PubMed 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 ( = 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.

PubMed: 34055219
DOI: 10.1021/acsmedchemlett.0c00657

Experimental method

X-RAY DIFFRACTION (1.904 Å)