Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific thiol oxidoreductase ERp57

Abstract

Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity. Herein we identify the antiprotozoal/antimicrobial nitazoxanide as a potential anti-paramyxovirus drug targeting the F-protein. We show that nitazoxanide and its circulating-metabolite tizoxanide act at post-entry level by provoking Sendai virus and RSV F-protein aggregate formation, halting F-trafficking to the host plasma membrane. F-protein folding depends on ER-resident glycoprotein-specific thiol-oxidoreductase ERp57 for correct disulfide-bond architecture. We found that tizoxanide behaves as an ERp57 non-competitive inhibitor; the putative drug binding-site was located at the ERp57-b/b′ non-catalytic domains interface. ERp57-silencing mimicked thiazolide-induced F-protein alterations, suggesting an important role of this foldase in thiazolides anti-paramyxovirus activity. Nitazoxanide is used in the clinic as a safe and effective antiprotozoal/antimicrobial drug; its antiviral activity was shown in patients infected with hepatitis-C virus, rotavirus and influenza viruses. Our results now suggest that nitazoxanide may be effective also against paramyxovirus infection.

Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain

“…Due to its favorable safety proଏle (only few side effects are known), several studies addressed NTZ drug repurposing. Of interest, NTZ is also active against a broad range of anaerobic bacteria, like Helicobacter pylori and Clostridium difଏcile [7][8][9][10], replicating and nonreplicating Mycobacterium tuberculosis [11][12][13], helminths [14][15][16][17][18] as well as viruses [19][20][21][22][23][24]. Surprisingly, several studies also reported NTZ as a potential anticancer agent [25,26].…”

Medicinal chemistry strategies toward host targeting antiviral agents

“…It also showed no effect on cardiac repolarization in a clinical trial for cardiac safety. 69 In recent studies, 32 was revealed as a promising antiviral agent against a wide range of pathogenic viruses including influenza virus, 70 HBV, 71 HCV, 71 EBOV, 72 DENV, 73 JEV, 74 HIV, 75 and ZIKV, 76 among others with IC 50 values ranging from 0.06 to 1.0 μg/mL 77,78 Its mechanism studies revealed that multiple host antiviral pathways were involved, and as such 32 is widely known as a polypharmacology antiviral agent. 32 activated protein kinase R (PKR), which plays vital roles in innate immune system.…”

Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference

“…Randomized phase 2 study evaluating nitazoxanide versus placebo in hospitalized subjects with severe acute respiratory illness John Beigel, NIAID, Bethesda, MD, USA. Nitazoxanide (NTZ) is a small inhibitor used extensively for treatment of Giardia and Cryptosporidium infections, and is being explored for the treatment of influenza and other influenza-like illnesses (ILI) (Rossignol, 2014;Shakya et al, 2018) such as parainfluenza (PIV), RSV, canine coronavirus, rhinovirus and influenza (Haffizulla et al, 2014;Piacentini et al, 2018;Rossignol, 2014;Stachulski et al, 2017). Moreover, NTZ is shown to be synergistic with oseltamivir and zanamivir (Belardo et al, 2011).…”