7O55

Crystal Structure of Unlinked NS2B-NS3 Protease from Zika Virus in Complex with Inhibitor MI-2231

Summary for 7O55

• Entry DOI: 10.2210/pdb7o55/pdb
• Descriptor: Serine protease subunit NS2B, Serine protease NS3, Inhibitor MI-2231, ... (4 entities in total)
• Functional Keywords: flavirin, serine protease, viral protein, ns2b-ns3, zika virus
• Biological source: Zika virus (ZIKV); More
• Total number of polymer chains: 3
• Total formula weight: 25548.77

Authors

Huber, S.,Heine, A.,Steinmetzer, T. (deposition date: 2021-04-07, release date: 2022-04-06, Last modification date: 2024-01-31)

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 (1.95 Å)