Abstract:
:Flaviviruses causes significant human disease. Recent outbreaks of the Zika virus highlight the need to develop effective therapies for this class of viruses. Previously we identified niclosamide as a broad-spectrum inhibitor for flaviviruses by targeting the interface between viral protease NS3 and its cofactor NS2B. Here, we screened a small library of niclosamide derivatives and identified a new analogue with improved pharmacokinetic properties. Compound JMX0207 showed improved efficacy in inhibition of the molecular interaction between NS3 and NS2B, better inhibition of viral protease function, and enhanced antiviral efficacy in the cell-based antiviral assay. The derivative also significantly reduced Zika virus infection on 3D mini-brain organoids derived from pluripotent neural stem cells. Intriguingly, the compound significantly reduced viremia in a Zika virus (ZIKV) animal model. In summary, a niclosamide derivative, JMX0207, was identified, which shows improved pharmacokinetics and efficacy against Zika virus both in vitro and in vivo.
journal_name
ACS Infect Disjournal_title
ACS infectious diseasesauthors
Li Z,Xu J,Lang Y,Fan X,Kuo L,D'Brant L,Hu S,Samrat SK,Trudeau N,Tharappel AM,Rugenstein N,Koetzner CA,Zhang J,Chen H,Kramer LD,Butler D,Zhang QY,Zhou J,Li Hdoi
10.1021/acsinfecdis.0c00217subject
Has Abstractpub_date
2020-10-09 00:00:00pages
2616-2628issue
10issn
2373-8227journal_volume
6pub_type
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