Discovery of Zika Virus NS2B/NS3 Inhibitors That Prevent Mice from Life-Threatening Infection and Brain Damage

Abstract

Zika virus (ZIKV) infection, which initially was endemic only in Africa and Asia, is rapidly spreading throughout Europe, Oceania, and the Americas. Although there have been enormous efforts, there is still no approved drug to treat ZIKV infection. Herein, we report the synthesis and biological evaluation of agents with noncompetitive mechanism of the ZIKV NS2B/NS3 protease inhibition through the binding to an allosteric site. Compounds 1 and 2 showed potent activity in both enzymatic and cellular assays. Derivative 1 efficiently reduced the ZIKV protein synthesis and the RNA replication and prevented the mice from life-threatening infection and the brain damage caused by ZIKV infection in a ZIKV mouse model.

NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

“…The variables of interest extracted from the selected studies are summarized in Table 1, and the results were grouped based on the anti‐ZIKV activity of the compounds. The studies were published in 2017 (5/14; 36%), 41,42,45–47 2018–2019 (3/14; 21%), 43,44,54 and 2020–2021 (6/14; 43%) 48–53 . The antiviral activities of the identified compounds were analyzed based on their ability to inhibit the NS2B‐NS3 pro complex through protein thermal exchange assays (2/14; 14%), 41,45 fluorescent peptide substrate assay (9/14; 65%), 42,44,46–50,53,54 X‐ray (1/14; 7%), 43 and fluorescence resonance energy transfer (2/14; 14%) 51,52 .…”

“…The IC 50 values for the inhibition of ZIKV NS2B‐NS3 pro ranged at 0.2–158 µM, in which the lowest IC 50 was reported for a compound generically called Compound 9 (Table 1, Entry 3) 43 . Most compounds showed noncompetitive inhibition (16/17; 94%), 41,44–46,48–54 and only novobiocin (Table 1, Entry 9) showed competitive inhibition (1/17; 6%) 47 . Among the noncompetitive inhibitors, five compounds (Table 1, Entries 4, 5, 6, 7, and 17) (5/17; 23.5%) were orthosteric inhibitors 44,45,54 .…”

“…Part of the intermolecular interactions between the enzyme and compounds did not have a well-defined chemical bond. [41][42][43][44][45][46][48][49][50][51][52][53][54] In this context, 12 studies described the intermolecular interactions, such as hydrogen and hydrophobic bonds, involved in the activity of the compounds. 41,43,44,[46][47][48][49][50][51][52][53][54] Five compounds (Table 1, Entries 4, 5, 6, 7, and 17) showed the ability to interact with a region called 2B53 in NS3 (5/17, 29%), which contains essential amino acid residues to bind to NS2B.…”

“…The studies were published in 2017 (5/14; 36%), 41,42,[45][46][47] 2018-2019 (3/14; 21%), 43,44,54 and 2020-2021 (6/14; 43%). [48][49][50][51][52][53] The antiviral activities of the identified compounds were analyzed based on their ability to inhibit the NS2B-NS3 pro complex through protein thermal exchange assays (2/14; 14%), 41,45 T A B L E 1 Summary of chemical structures and biological proprieties of compounds with inhibitory activity against ZIKV NS2B-NS3 pro | 447 fluorescent peptide substrate assay (9/14; 65%), 42,44,[46][47][48][49][50]53,54 X-ray (1/14; 7%), 43 and fluorescence resonance energy transfer (2/14; 14%). 51,52 The IC 50 values for the inhibition of ZIKV NS2B-NS3 pro ranged at 0.…”

“…[41][42][43][44][45][46][48][49][50][51][52][53][54] In this context, 12 studies described the intermolecular interactions, such as hydrogen and hydrophobic bonds, involved in the activity of the compounds. 41,43,44,[46][47][48][49][50][51][52][53][54] Five compounds (Table 1, Entries 4, 5, 6, 7, and 17) showed the ability to interact with a region called 2B53 in NS3 (5/17, 29%), which contains essential amino acid residues to bind to NS2B. Therefore, it is suggested that these compounds inhibit the NS3-NS2B pro interaction, which is crucial for the catalytic activity of this protease.…”