Structure‐Based Macrocyclization of Substrate Analogue NS2B‐NS3 Protease Inhibitors of Zika, West Nile and Dengue viruses

A series of cyclic active‐site‐directed inhibitors of the NS2B‐NS3 proteases from Zika (ZIKV), West Nile (WNV), and dengue‐4 (DENV4) viruses has been designed. The most potent compounds contain a reversely incorporated d‐lysine residue in the P1 position. Its side chain is connected to the P2 backbo...

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Veröffentlicht in:	ChemMedChem 2020-08, Vol.15 (15), p.1439-1452
Hauptverfasser:	Braun, Niklas J., Quek, Jun P., Huber, Simon, Kouretova, Jenny, Rogge, Dorothee, Lang‐Henkel, Heike, Cheong, Ezekiel Z. K., Chew, Bing L. A., Heine, Andreas, Luo, Dahai, Steinmetzer, Torsten
Format:	Artikel
Sprache:	eng
Schlagworte:	Chains Crystal structure Cyclic compounds Dengue fever dengue virus Dengue Virus - enzymology Dose-Response Relationship, Drug drug design Guanidine Lysine Macrocyclic Compounds - chemical synthesis Macrocyclic Compounds - chemistry Macrocyclic Compounds - pharmacology Molecular Structure NS2B-NS3 protease Peptides - chemical synthesis Peptides - chemistry Peptides - pharmacology Proprotein convertases Protease Protease inhibitors Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Proteinase inhibitors Residues RNA Helicases - antagonists & inhibitors RNA Helicases - metabolism Selectivity Serine Serine Endopeptidases - metabolism Structure-Activity Relationship Substrate inhibition Trypsin Vector-borne diseases Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - metabolism Viruses West Nile virus West Nile virus - enzymology Zika virus Zika Virus - enzymology
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Zusammenfassung:	A series of cyclic active‐site‐directed inhibitors of the NS2B‐NS3 proteases from Zika (ZIKV), West Nile (WNV), and dengue‐4 (DENV4) viruses has been designed. The most potent compounds contain a reversely incorporated d‐lysine residue in the P1 position. Its side chain is connected to the P2 backbone, its α‐amino group is converted into a guanidine to interact with the conserved Asp129 side chain in the S1 pocket, and its C terminus is connected to the P3 residue via different linker segments. The most potent compounds inhibit the ZIKV protease with Ki values
ISSN:	1860-7179 1860-7187
DOI:	10.1002/cmdc.202000237