7VLH

Crystal structure of Zika NS2B-NS3 protease with compound MI2219

Summary for 7VLH

• Entry DOI: 10.2210/pdb7vlh/pdb
• Descriptor: Serine protease subunit NS2B, NS3 protease, 1-[(3~{S},6~{R},18~{R})-3,6-bis(4-azanylbutyl)-2,5,8,11,14,17-hexakis(oxidanylidene)-1,4,7,10,13,16-hexazacyclodocos-18-yl]guanidine, ... (5 entities in total)
• Functional Keywords: ns3 protease, viral protein
• Biological source: Zika virus (ZIKV); More
• Total number of polymer chains: 2
• Total formula weight: 25596.75

Authors

Quek, J.P. (deposition date: 2021-10-02, release date: 2022-08-10, Last modification date: 2024-10-23)

Primary citation

Huber, S.,Braun, N.J.,Schmacke, L.C.,Quek, J.P.,Murra, R.,Bender, D.,Hildt, E.,Luo, D.,Heine, A.,Steinmetzer, T.
Structure-Based Optimization and Characterization of Macrocyclic Zika Virus NS2B-NS3 Protease Inhibitors.
J.Med.Chem., 65:6555-6572, 2022

PubMed Abstract: Zika virus (ZIKV) is a human pathogenic arbovirus. So far, neither a specific treatment nor a vaccination against ZIKV infections has been approved. Starting from our previously described lead structure, a series of 29 new macrocyclic inhibitors of the Zika virus protease containing different linker motifs have been synthesized. By selecting hydrophobic d-amino acids as part of the linker, numerous inhibitors with values < 5 nM were obtained. For 12 inhibitors, crystal structures in complex with the ZIKV protease up to 1.30 Å resolution were determined, which contribute to the understanding of the observed structure-activity relationship (SAR). In immunofluorescence assays, an antiviral effect was observed for compound containing a d-homocyclohexylalanine residue in its linker segment. Due to its excellent selectivity profile and low cytotoxicity, this inhibitor scaffold could be a suitable starting point for the development of peptidic drugs against the Zika virus and related flaviviruses.

PubMed: 35475620
DOI: 10.1021/acs.jmedchem.1c01860

Experimental method

X-RAY DIFFRACTION (2.621 Å)