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.
Highlights
The Paramyxoviridae form an increasingly diverse family of old and emerging viruses responsible for a wide range of animal and human diseases, including the causative agents of mumps, measles and several respiratory tract infections due to parainfluenza viruses, metapneumoviruses, respiratory syncytial virus (RSV), as well as pathogens responsible for some of the deadliest emerging zoonoses, such as Hendra and Nipah viruses[1,2]
Sendai virus (SeV) 15,384-bases genome is associated with the nucleocapsid-N protein forming a helical ribonucleoprotein structure (RNP) that serves as template for mRNA transcription and genome replication
Nitazoxanide (Fig. 1A) antiviral activity was initially investigated in monkey kidney (AGMK) cells infected with Sendai virus (SeV) under single-step or multistep conditions
Summary
The Paramyxoviridae form an increasingly diverse family of old and emerging viruses responsible for a wide range of animal and human diseases, including the causative agents of mumps, measles and several respiratory tract infections due to parainfluenza viruses, metapneumoviruses, respiratory syncytial virus (RSV), as well as pathogens responsible for some of the deadliest emerging zoonoses, such as Hendra and Nipah viruses[1,2]. Nitazoxanide (Fig. 1A) antiviral activity was initially investigated in monkey kidney (AGMK) cells infected with Sendai virus (SeV) under single-step or multistep conditions.
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