ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity

Xia, Zhiqiang; Wang, Luyao; Li, Songryong; Tang, Wei; Sun, Fang; Wu, Yingliang; Miao, Lei; Cao, Zhijian

doi:10.1016/j.antiviral.2020.104922

Cited by 31 publications

(16 citation statements)

References 47 publications

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“…Six main targets were classified: receptor tyrosine kinase (RTK), 20S proteasome β5, ion channel, DNA synthesis, antibacteria or protozoa drugs and natural products ( Figure 1 b). Numerous studies report RTK inhibitors, ion channel inhibitors, DNA synthesis inhibitors, antibacteria or protozoa drugs and natural products to be arbovirus antivirals [ 14 , 15 , 16 , 17 ]. However, little work has been conducted regarding 20S proteasome β5 inhibitors as direct-acting antivirals.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Screening of FDA-Approved Drug Library Reveals Ixazomib Is a Broad-Spectrum Antiviral Agent against Arboviruses

Ding¹,

Tang²,

Binghui³

et al. 2022

Viruses

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The emergence of significant arboviruses and their spillover transmission to humans represent a major threat to global public health. No approved drugs are available for the treatment of significant arboviruses in circulation today. The repurposing of clinically approved drugs is one of the most rapid and promising strategies in the identification of effective treatments for diseases caused by arboviruses. Here, we screened small-molecule compounds with anti-tick-borne encephalitis virus, West Nile virus, yellow fever virus and chikungunya virus activity from 2580 FDA-approved drugs. In total, 60 compounds showed antiviral efficacy against all four of the arboviruses in Huh7 cells. Among these compounds, ixazomib and ixazomib citrate (inhibitors of 20S proteasome β5) exerted antiviral effects at a low-micromolar concentration. The time-of-drug-addition assay suggested that ixazomib and ixazomib citrate disturbed multiple processes in viruses’ life cycles. Furthermore, ixazomib and ixazomib citrate potently inhibited chikungunya virus replication and relieved virus-induced footpad swelling in a mouse model. These results offer critical information which supports the role of ixazomib as a broad-spectrum agent against arboviruses.

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Section: Resultsmentioning

confidence: 99%

High-Throughput Screening of FDA-Approved Drug Library Reveals Ixazomib Is a Broad-Spectrum Antiviral Agent against Arboviruses

Ding¹,

Tang²,

Binghui³

et al. 2022

Viruses

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“…Our mmTRPML2 structure in the apo state, obtained in lipid nanodiscs, which mimic the native cellular environment, will contribute to a deeper understanding of channel gating mechanisms and corresponding biological mutational effects. It is known that TRPMLs can be activated by ML-SA1 and endogenous PI(3,5)P 2 , while can be inhibited by PI(4,5)P 2 and sphingomyelins ( 40 , 41 , 42 ). The extracellular/luminal pH, calcium, and other factors have also been reported to modulate the gating of TRPML channels ( 40 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of mouse TRPML2 in lipid nanodiscs

Song

Tian

et al. 2022

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Anke Di et al found that the cystic fibrosis transmembrane conductance regulator Cl-channel (CFTR) contributes to lysosomal acidification (Di et al, 2006). Zhiqiang Xia et al found that ML-SA1, a TRPML agonist, inhibits dengue virus (DENV) and Zika virus (ZIKV) in vitro by promoting lysosomal acidification (Xia et al, 2020). Liang Hui (Sasikumar et al, 2019).…”

Section: Other Ion Channels In Lysosome Membranementioning

confidence: 99%

Role of Lysosomal Acidification Dysfunction in Mesenchymal Stem Cell Senescence

Zhang

Bai

Hang

et al. 2022

Front. Cell Dev. Biol.

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Mesenchymal stem cell (MSC) transplantation has been widely used as a potential treatment for a variety of diseases. However, the contradiction between the low survival rate of transplanted cells and the beneficial therapeutic effects has affected its clinical use. Lysosomes as organelles at the center of cellular recycling and metabolic signaling, play essential roles in MSC homeostasis. In the first part of this review, we summarize the role of lysosomal acidification dysfunction in MSC senescence. In the second part, we summarize some of the potential strategies targeting lysosomal proteins to enhance the therapeutic effect of MSCs.

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ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity

Cited by 31 publications

References 47 publications

High-Throughput Screening of FDA-Approved Drug Library Reveals Ixazomib Is a Broad-Spectrum Antiviral Agent against Arboviruses

High-Throughput Screening of FDA-Approved Drug Library Reveals Ixazomib Is a Broad-Spectrum Antiviral Agent against Arboviruses

Cryo-EM structure of mouse TRPML2 in lipid nanodiscs

Role of Lysosomal Acidification Dysfunction in Mesenchymal Stem Cell Senescence

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