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

• Published in: Journal of medical virology Vol. 94; no. 2; pp. 442 - 453
• Main Authors: Nunes, Damiana Antônia de Fátima, Santos, Felipe Rocha da Silva, Fonseca, Sara Thamires Dias, Lima, William Gustavo, Nizer, Waleska Stephanie da Cruz, Ferreira, Jaqueline Maria Siqueira, Magalhães, José Carlos
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2022
• Subjects: Animals; antiviral; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Bromocriptine; Cell lines; Complications; Cytotoxicity; Drugs; enzymatic inhibition; Humans; Molecular Targeted Therapy; Neurological complications; Niclosamide; noncompetitive inhibitors; Novobiocin; NS2B‐NS3 protease; Pharmacodynamics; Pharmacology; Protease; Protease inhibitors; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Proteinase inhibitors; Public health; Replication; Reviews; Selectivity; Systematic review; Vaccines; Vector-borne diseases; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virology; Virus Replication - drug effects; Viruses; Zika virus; Zika Virus - drug effects; Zika Virus - enzymology; Zika Virus Infection - drug therapy; Zika Virus Infection - virology; Zika virus; enzymatic inhibition; noncompetitive inhibitors; NS2B-NS3 protease; antiviral
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.27386

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.