Structure-Based Optimization and Characterization of Macrocyclic Zika Virus NS2B-NS3 Protease Inhibitors

  • J Med Chem. 2022 May 12;65(9):6555-6572. doi: 10.1021/acs.jmedchem.1c01860.
Simon Huber  1 ,  Niklas J Braun  1 ,  Luna C Schmacke  1 ,  Jun Ping Quek  2  3 ,  Robin Murra  4 ,  Daniela Bender  4 ,  Eberhard Hildt  4 ,  Dahai Luo  2  3  5 ,  Andreas Heine  1 ,  Torsten Steinmetzer  1
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Philipps University of Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
  • 2. Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, Singapore 636921.
  • 3. NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, Singapore 636921.
  • 4. Federal Institute for Vaccines and Biomedicines, Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany.
  • 5. School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
PMID: 35475620 DOI: 10.1021/acs.jmedchem.1c01860
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 Ki 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 26 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.

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