6KK3

Crystal structure of Zika NS2B-NS3 protease with compound 4

Summary for 6KK3

• Entry DOI: 10.2210/pdb6kk3/pdb
• Descriptor: Genome polyprotein, 1-[(10~{R},17~{S},20~{S})-17,20-bis(4-azanylbutyl)-4,9,16,19,22-pentakis(oxidanylidene)-3,8,15,18,21-pentazabicyclo[22.2.2]octacosa-1(26),24,27-trien-10-yl]guanidine, ... (4 entities in total)
• Functional Keywords: viral protease, protease inhibitor complex, viral protein
• Biological source: Zika virus (ZIKV); More
• Total number of polymer chains: 2
• Total formula weight: 21377.17

Authors

Quek, J.P. (deposition date: 2019-07-23, release date: 2020-06-17, Last modification date: 2023-11-22)

Primary citation

Braun, N.J.,Quek, J.P.,Huber, S.,Kouretova, J.,Rogge, D.,Lang-Henkel, H.,Cheong, E.Z.K.,Chew, B.L.A.,Heine, A.,Luo, D.,Steinmetzer, T.
Structure-Based Macrocyclization of Substrate Analogue NS2B-NS3 Protease Inhibitors of Zika, West Nile and Dengue viruses.
Chemmedchem, 15:1439-1452, 2020

PubMed Abstract: 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 K 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.

PubMed: 32501637
DOI: 10.1002/cmdc.202000237

Experimental method

X-RAY DIFFRACTION (2.05 Å)