Identification of covalent active site inhibitors of dengue virus protease

Xiaoying Koh-Stenta; Joma Joy; Si Fang Wang; Perlyn Zekui Kwek; John Liang Kuan Wee; Kah Fei Wan; Shovanlal Gayen; Angela Shuyi Chen; CongBao Kang; May Ann Lee; Anders Poulsen; Subhash G Vasudevan; Jeffrey Hill; Kassoum Nacro

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Identification of covalent active site inhibitors of dengue virus protease

机译：登革热病毒蛋白酶共价活性位点抑制剂的鉴定

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Dengue virus (DENV) protease is an attractive target for drug development; however, no compounds have reached clinical development to date. In this study, we utilized a potent West Nile virus protease inhibitor of the pyrazole ester derivative class as a chemical starting point for DENV protease drug development. Compound potency and selectivity for DENV protease were improved through structure-guided small molecule optimization, and protease-inhibitor binding interactions were validated biophysically using nuclear magnetic resonance. Our work strongly suggests that this class of compounds inhibits flavivirus protease through targeted covalent modification of active site serine, contrary to an allosteric binding mechanism as previously described.

机译：登革热病毒（DENV）蛋白酶是药物开发的诱人靶标;然而，迄今为止，还没有化合物达到临床开发。在这项研究中，我们利用了吡唑酯衍生物类的有效西尼罗河病毒蛋白酶抑制剂作为DENV蛋白酶药物开发的化学起点。通过结构引导的小分子优化，提高了DENV蛋白酶的化合物效能和选择性，并使用核磁共振通过生物物理方法验证了蛋白酶抑制剂的结合相互作用。我们的工作强烈建议这类化合物通过活性位点丝氨酸的靶向共价修饰来抑制黄病毒蛋白酶，这与前述的变构结合机制相反。

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《Drug Design, Development and Therapy》 |2015年第9期|共11页
作者
Xiaoying Koh-Stenta; Joma Joy; Si Fang Wang; Perlyn Zekui Kwek; John Liang Kuan Wee; Kah Fei Wan; Shovanlal Gayen; Angela Shuyi Chen; CongBao Kang; May Ann Lee; Anders Poulsen; Subhash G Vasudevan; Jeffrey Hill; Kassoum Nacro;
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中图分类药学;
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1. Identification of a loop outside the active site cavity of the human immunodeficiency virus proteases which confers inhibitor specificity. [J] . Towler EM, Thompson SK, Tomaszek T, Biochemistry . 1997,第17期

机译：鉴定人免疫缺陷病毒蛋白酶活性位点腔外的环，该环赋予抑制剂特异性。
2. Active site cavity of herpesvirus proteases revealed by the crystal structure of herpes simplex virus protease/inhibitor complex [J] . Hoog SS, Smith WW, Qiu X, Biochemistry . 1997,第46期

机译：单纯疱疹病毒蛋白酶/抑制剂复合物的晶体结构揭示了疱疹病毒蛋白酶的活性位点腔
3. Structure-guided mutagenesis of active site residues in the dengue virus two-component protease NS2B-NS3 [J] . Wanisa Salaemae, Muhammad Junaid, Chanan Angsuthanasombat, Journal of biomedical science. . 2010,第1期

机译：登革热病毒两成分蛋白酶NS2B-NS3中活性位点残基的结构指导诱变
4. Virtual screening of commercial cyclic peptides as NS2B-NS3 protease inhibitor of dengue virus serotype 2 through molecular docking simulation [C] . M A F Nasution, R N Aini, U S F Tambunan International Symposium on Current Progress in Functional Materials . 2017

机译：通过分子对接模拟为Dengue病毒血清型2的NS2B-NS3蛋白酶抑制剂的虚拟筛选
5. Development of Protease Inhibitors to Combat Dengue and West Nile Viruses [D] . Tomlinson, Suzanne Marie 2010

机译：蛋白酶抑制剂对抗登革热和西尼罗河病毒的发展
6. Identification of covalent active site inhibitors of dengue virus protease [O] . Xiaoying Koh-Stenta, Joma Joy, Si Fang Wang, 2015

机译：登革热病毒蛋白酶共价活性位点抑制剂的鉴定
7. In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2 [O] . Sekiou Omar, Ismail Bouziane, Zihad Bouslama, 2020

机译：来自天然产物的Covid-19主要蛋白酶（MPRO）和血管紧张素转化酶2（ACE2）的二氧化硅鉴定：槲皮素，幼稚蛋白和肝癌比羟基 - 氯喹对Covid-19主要蛋白酶活性位点更好地抑制潜在的抑制作用和ace2.

Identification of covalent active site inhibitors of dengue virus protease

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