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

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Structure-Based Macrocyclization of Substrate Analogue NS2B-NS3 Protease Inhibitors of Zika, West Nile and Dengue viruses.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-06-05 , DOI: 10.1002/cmdc.202000237
Niklas J Braun ₁ , Jun P Quek _{2,

3} , Simon Huber ₁ , Jenny Kouretova ₁ , Dorothee Rogge ₁ , Heike Lang-Henkel ₁ , Ezekiel Z K Cheong ₄ , Bing L A Chew _{2,

3,

5} , Andreas Heine ₁ , Dahai Luo _{2,

3,

4} , Torsten Steinmetzer ₁

Affiliation

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 _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.

中文翻译：

寨卡病毒、西尼罗河病毒和登革热病毒的底物类似物 NS2B-NS3 蛋白酶抑制剂的基于结构的大环化。

设计了一系列寨卡病毒 (ZIKV)、西尼罗河病毒 (WNV) 和登革热 4 (DENV4) 病毒 NS2B-NS3 蛋白酶的环状活性位点定向抑制剂。最有效的化合物在 P1 位上含有反向掺入的d-赖氨酸残基。其侧链连接至P2主链，其α-氨基转化为胍以与S1口袋中保守的Asp129侧链相互作用，其C末端通过不同的接头片段连接至P3残基。最有效的化合物可抑制 ZIKV 蛋白酶， K _i值<5 nM。确定了七种 ZIKV 蛋白酶抑制剂复合物的晶体结构以支持抑制剂设计。所有环状化合物均对胰蛋白酶样丝氨酸蛋白酶和弗林蛋白酶样前蛋白转化酶具有高选择性。 WNV 和 DENV4 蛋白酶的抑制效率较低。尽管如此，这些酶观察到了类似的结构-活性关系，因此表明它们作为泛黄病毒蛋白酶抑制剂的潜在应用。

更新日期：2020-08-05

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