Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage

Zhang, Xin; Liu, Qiang; Zhang, Na; Li, Qian–Qian; Liu, Zhan–Dong; Li, Yinghong; Gao, Lei; Wang, You–Chun; Deng, Hongbin; Song, Dan–Qing

doi:10.1016/j.ejmech.2018.02.061

Cited by 35 publications

(26 citation statements)

References 34 publications

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“…Multiple compounds have been shown to interfere with different steps of the EBOV lifecycle [34], including inhibitors of cellular cysteine proteases [32,[35][36][37][38][39]. However, none of these compounds has been approved by regulatory agencies for treatment of EVD.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins

et al. 2019

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Ebola virus (EBOV) infection can cause severe and frequently fatal disease in human patients. The EBOV glycoprotein (GP) mediates viral entry into host cells. For this, GP depends on priming by the pH-dependent endolysosomal cysteine proteases cathepsin B (CatB) and, to a lesser degree, cathepsin L (CatL), at least in most cell culture systems. However, there is limited information on whether and how EBOV-GP can acquire resistance to CatB/L inhibitors. Here, we addressed this question using replication-competent vesicular stomatitis virus bearing EBOV-GP. Five passages of this virus in the presence of the CatB/CatL inhibitor MDL28170 were sufficient to select resistant viral variants and sequencing revealed that all GP sequences contained a V37A mutation, which, in the context of native GP, is located in the base of the GP surface unit. In addition, some GP sequences harbored mutation S195R in the receptor-binding domain. Finally, mutational analysis demonstrated that V37A but not S195R conferred resistance against MDL28170 and other CatB/CatL inhibitors. Collectively, a single amino acid substitution in GP is sufficient to confer resistance against CatB/CatL inhibitors, suggesting that usage of CatB/CatL inhibitors for antiviral therapy may rapidly select for resistant viral variants. envelope with the limiting membrane of endolysosomes [12], allowing delivery of the viral genome into the host cell cytoplasm. Binding and membrane fusion are carried out by different subunits of GP. The N-terminal surface unit, GP1, binds to host cell receptors via a receptor-binding domain (RBD), while the C-terminal transmembrane unit, GP2, harbors the functional elements required for membrane fusion, including a fusion peptide and heptad repeats [10]. Although GP1 can bind to attachment factors on the cell surface [13,14], only the interaction with the intracellular receptor Niemann-Pick C1 (NPC1) within host cell endolysosomes is essential for EBOV entry [13][14][15][16]. This interaction critically depends on previous processing of EBOV-GP by the endolysosomal, pH-dependent cysteine proteases cathepsin B (CatB) and cathepsin L (CatL) [15][16][17][18]. Processing removes a glycan cap and a mucin-like domain (MLD) from GP1 and results in a primed form of GP. Primed GP still contains the RBD linked to GP2 via a disulfide bond [19,20] and can fuse the viral membrane with an endolysosomal membrane upon receipt of a trigger. However, the nature of this trigger remains to be identified [21][22][23][24].In the light of the important role of CatB/CatL in EBOV-GP-driven entry, inhibitors targeting these enzymes might hold therapeutic potential, although it should be stated that CatB/CatL dependence varies between filoviruses [25,26] and target cell types [27] and was not observed in experimentally infected mice [28]. A previous study employed a replication-competent VSV chimera bearing EBOV-GP without MLD (VSV-EBOV) to examine resistance development against the CatB inhibitor CA074 [29]. Resistance development was observed after two pa...

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Section: Discussionmentioning

confidence: 99%

Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins

et al. 2019

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“…Several compounds with anti-EBOV entry properties were also selected after a screening analysis by Anantpadama and co-workers [106]. In addition, lead compounds can be also derived by the screening of Chinese natural herbs used in the traditional medicine [107,108].…”

Section: Ebola Virus Entry Inhibitorsmentioning

confidence: 99%

Ebola Virus Entry: From Molecular Characterization to Drug Discovery

Salata

Calistri

Alvisi

et al. 2019

Viruses

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Ebola Virus Disease (EVD) is one of the most lethal transmissible infections, characterized by a high fatality rate, and caused by a member of the Filoviridae family. The recent large outbreak of EVD in Western Africa (2013–2016) highlighted the worldwide threat represented by the disease and its impact on global public health and the economy. The development of highly needed anti-Ebola virus antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, allowing to screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to study Ebola virus entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus-like particles, tremendously boosted both our knowledge of the viral life cycle and the identification of promising antiviral compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD.

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“…These inhibitors include the cysteine-serine protease inhibitor leupeptin, cysteine protease inhibitors E64, E64a, E64d, K11777 and K11777-derivatives, cathepsin B inhibitors CA074 and CA074Me and cathepsin L inhibitor III [83,84,[101][102][103][104][105]. Several more studies have been undertaken to identify inhibitors of cathepsin B and L cleavage of GP and inhibition of filovirus entry [106][107][108]. These include the natural product aloperine and its derivatives which target cathepsin B and the glycopeptide antibiotic teicoplanin that is suggested to inhibit cathepsin L. Finally, it should be noted that cathepsins B and L are activated by low pH and inhibitors of endosomal acidification also inhibit filovirus entry [109,110].…”

Section: Inhibitors Of Cathepsinsmentioning

confidence: 99%

Current status of small molecule drug development for Ebola virus and other filoviruses

Edwards

Basler

2019

Current Opinion in Virology

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The filovirus family includes some of the deadliest viruses known, including Ebola virus and Marburg virus. These viruses cause periodic outbreaks of severe disease that can be spread from person to person, making the filoviruses important public health threats. There remains a need for approved drugs that target all or most members of this virus family. Small molecule inhibitors that target conserved functions hold promise as pan-filovirus therapeutics. To date, compounds that effectively target virus entry, genome replication, gene expression and virus egress have been described. The most advanced inhibitors are nucleoside analogs that target viral RNA synthesis reactions.

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Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage

Cited by 35 publications

References 34 publications

Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins

Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins

Ebola Virus Entry: From Molecular Characterization to Drug Discovery

Current status of small molecule drug development for Ebola virus and other filoviruses

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