Journal
CHEMMEDCHEM
Volume 15, Issue 15, Pages 1439-1452Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000237
Keywords
dengue virus; drug design; NS2B-NS3 protease; Zika virus; West Nile virus
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Funding
- LOEWE Center DRUID (Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases)
- Lee Kong Chian School of Medicine, Nanyang Technological University
- Singapore National Research Foundation grant [NRF2016NRF-CRP001-063]
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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 incorporatedd-lysine residue in the P1 position. Its side chain is connected to the P2 backbone, its alpha-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 withK(i)values <5 nM. Crystal structures of seven ZIKV protease inhibitor complexes were determined to support the inhibitor design. All the cyclic compounds possess high selectivity against trypsin-like serine proteases and furin-like proprotein convertases. Both WNV and DENV4 proteases are inhibited less efficiently. Nonetheless, similar structure-activity relationships were observed for these enzymes, thus suggesting their potential application as pan-flaviviral protease inhibitors.
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