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Identification of NMS-873, an Allosteric and Specific p97 Inhibitor, as a Broad Antiviral Against Both Influenza A and B Viruses

Identification of NMS-873, an Allosteric and Specific p97 Inhibitor, as a Broad Antiviral Against Both Influenza A and B Viruses

Jiantao Zhang, Yanmei Hu, Raymond Hau, Rami Musharrafieh, Chunlong Ma, Xu Zhou, Yin Chen, Jun Wang

Eur J Pharm Sci. 2019 May 15;133:86-94.

PMID: 30930289

Abstract:

Influenza virus infection causes substantial morbidity and mortality worldwide. The limited efficacy of oseltamivir in delayed treatment, coupled with the increasing incidences of oseltamivir-resistant strains, calls for next-generation of antiviral drugs. In this study, we discovered NMS-873, an allosteric and specific p97 inhibitor, as a broad-spectrum influenza antiviral through forward chemical genomics screening. NMS-873 shows potent antiviral activity with low-nanomolar EC50s against multiple human influenza A and B viruses, including adamantine-, oseltamivir-, or double resistant strains. Our data further showed that silencing of p97 via siRNA or inhibiting p97 by NMS-873 both inhibited virus replication and retained viral ribonucleoproteins (vRNPs) in the nucleus, confirming p97 is the drug target. Mechanistic studies have shown that the nuclear retention of vRNP with NMS-873 treatment is a combined result of two effects: the reduced viral M1 protein level (indirect effect), and the disruption of p97-NP interactions (direct effect). Taken together, our results suggest that p97 could be a novel antiviral target and its inhibitor, NMS-873, is a promising antiviral drug candidate.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1418013758	NMS-873		1418013-75-8	Price

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