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

Abstract

Zika virus (ZIKV) infections are associated with severe neurological complications and are a global public health concern. There are no approved vaccines or antiviral drugs to inhibit ZIKV replication. NS2B-NS3 protease (NS2B-NS3 pro), which is essential for viral replication, is a promising molecular target for anti-ZIKV drugs. We conducted a systematic review to identify compounds with promising effects against ZIKV; we discussed their pharmacodynamic and pharmacophoric characteristics. The online search, performed using the PubMed/MEDLINE and SCOPUS databases, yielded 56 articles; seven relevant studies that reported nine promising compounds with inhibitory activity against ZIKV NS2B-NS3 pro were selected. Of these, five (niclosamide, nitazoxanide, bromocriptine, temoporfin, and novobiocin) are currently available on the market and have been tested for off-label use against ZIKV. The 50% inhibitory concentration values of these compounds for the inhibition of NS2B-NS3 pro ranged at 0.38-21.6 µM; most compounds exhibited noncompetitive inhibition (66%). All compounds that could inhibit the NS2B-NS3 pro complex showed potent in vitro anti-ZIKV activity with a 50% effective concentration ranging 0.024-50 µM. The 50% cytotoxic concentration of the compounds assayed using A549, Vero, and WRL-69 cell lines ranged at 0.6-1388.02 µM and the selectivity index was 3.07-1698. This review summarizes the most promising antiviral agents against ZIKV that have inhibitory activity against viral proteases.

The Photosensitizer Temoporfin (mTHPC) – Chemical, Pre‐clinical and Clinical Developments in the Last Decade†‡

“…A promising development is the identification of temoporfin as a potential drug to inhibit the replication of the Zika virus (585). Initially endemic to Africa Zika infections have now spread and are a global health concern.…”

Crystallographic fragment screening delivers diverse chemical scaffolds for Zika virus NS2B-NS3 protease inhibitor development

“…Most of the reported competitive NS2B-NS3 inhibitors are limited to peptide mimics, such as macrocyclic inhibitors 13, 14 . Although these peptidomimetic inhibitors display nanomolar potency against ZIKV NS2B-NS3 protease, and some have broad spectrum antiviral activity, such as against DENV and WNV as well 15 , their cellular activity and pharmacokinetic properties are poor. The natural substrate preference for a dibasic residue motif also raises challenge for competitive inhibitor development.…”

Quinazolinone Compounds Have Potent Antiviral Activity against Zika and Dengue Virus

“…The only licensed DENV vaccine, Dengvaxia, has been found to have safety and efficacy concerns for DENV-naïve individuals in clinical trials . A limited number of compounds have been reported to have potent antiviral activities against ZIKV or DENV. − Most of these compounds are natural products with complex chemical structures that are not amenable to medicinal chemistry optimization. Only a few compounds showed broad activities against both ZIKV and DENV. − There is therefore a pressing need to find effective antiviral agents against ZIKV and DENV.…”

“…(Pyridin-4-yl)-3-(3-tert-butylphenyl)-2-[2-(6-methoxypyridin-2yl)vinyl]-4(3H)-quinazolinone dihydrochloride(29) 1. H NMR (CDCl 3 , 400 MHz) δ 8.71 (d, J = 5.4 Hz, 2H), 8.62 (d, J = 2.2 Hz, 1H), 8.08 (dd, J = 8.6, 2.2 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 14.8 Hz, 1H), 7.77−7.70 (m, 2H), 7.65 (ddd, J = 12.0, 8.2, 1.4 Hz, 1H), 7.58−7.43 (m, 4H), 7.32 (t, J = 1.9 Hz, 1H), 7.14 (ddd, J = 7.4, 2.2, 1.2 Hz, 1H), 7.04 (d, J = 14.8 Hz, 1H), 6.91 (d, J = 7.1 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 3.58 (s, 3H), 1.33 (s, 9H).…”