Discovery of Immunologically Inspired Small Molecules That Target the Viral Envelope Protein

Lian, Wenlong; Jang, Jaebong; Potisopon, Supanee; Li, Pi-Chun; Rahmeh, Amal; Wang, Jinhua; Kwiatkowski, Nicholas; Gray, Nathanael S.; Yang, Priscilla L.

doi:10.1021/acsinfecdis.8b00127

Cited by 21 publications

(28 citation statements)

References 34 publications

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“…We validated that YFVΔSK/Nluc gene expression was neutralized by YFV-specific antibodies and was dependent on several known pathways of flavivirus entry, including clathrin-and dynamin-mediated endocytosis (10,30,(65)(66)(67), endosomal acidification (45,(66)(67)(68)(69), E protein-dependent fusion (31), and dependence on LY6E (32,33) and RPLP1 (34).…”

Section: Discussionmentioning

confidence: 77%

“…As shown in Fig. 2G, YFV-mediated Nluc expression was sensitive to K784-9103, a small-molecule that binds to DENV E protein and inhibits membrane fusion of DENV and other flaviviruses (31). Furthermore, YFV-mediated Nluc expression was reduced by genetic ablation of LY6E ( Fig.…”

Section: Downloaded Frommentioning

confidence: 86%

“…The DENV fusion inhibitor K784-9103 was purchased from ChemDiv (San Diego, CA), and its structure and purity were confirmed by tandem liquid chromatography-mass spectrometry. Inhibition of E-mediated fusion was performed as previously described (31). Briefly, reporter viruses were incubated in medium containing the indicated concentrations of K784-9103 and then mixed in a rotary shaker for 30 min at room temperature to allow inhibitor to bind to virus particles before adding to cells.…”

Section: Discussionmentioning

confidence: 99%

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A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Ramanathan

Zhang

Douam

et al. 2020

mBio

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While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the postfusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replicationdefective yellow fever virus (YFV) entry reporter, YFVΔSK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFVΔSK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways and cellular factors, including clathrin-and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoprotein-mediated fusion, and cellular LY6E and RPLP1 expression. The initial round of YFV translation was shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid protein must be ubiquitylated in order for nucleocapsid uncoating to occur. Importantly, translation of incoming YFV genomes also required valosin-containing protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client proteins from large complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a postfusion, pretranslation step in YFV entry. Finally, VCP/p97 activity was required by other flaviviruses in mammalian cells and by YFV in mosquito cells. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a postfusion step in virus entry. IMPORTANCE Flaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here, we used a yellow fever virus entry reporter, which expresses a sensitive reporter enzyme but does not replicate, to show that nucleocapsid disassembly requires the cellular protein-disaggregating enzyme valosin-containing protein, also known as p97.

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Section: Discussionmentioning

confidence: 77%

Section: Downloaded Frommentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Ramanathan

Zhang

Douam

et al. 2020

mBio

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“…The life cycle of ZIKV involves several crucial steps, including viral attachment to target cell receptors or cofactors, receptor-mediated endocytosis (viral entry), virus–endosomal membrane fusion, and postentry or post-translation stages [9,10]. In this life cycle, E protein plays a key role in viral entry into target cells and subsequent fusion of virus and cell membranes; thus, ZIKV E protein serves as an important therapeutic target against ZIKV infection [11,12].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors

Gao

Tai

Wang

et al. 2019

Viruses

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Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.

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“…Porphyrins like Co-protoporphyrin IX (CoPPIX) and Sn-protoporphyrin IX (SnPPIX) induce viral envelope protein loss, affecting viral morphology and entry into target cells [81]. Benzoxazine monomer derived carbon dots (BZM-CDs) [82], polyoxometalates (POMs) [83], cyanohydrazones [84], synthetic carbohydrate receptors (SCRs) [85], and some other small molecules [86,87,88] also inhibit ZIKV infection in cell culture, and reduce viral replication in mice [89].…”

Section: Antiviralsmentioning

confidence: 99%

Therapeutic Advances Against ZIKV: A Quick Response, a Long Way to Go

Saiz

2019

Pharmaceuticals

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Zika virus (ZIKV) is a mosquito-borne flavivirus that spread throughout the American continent in 2015 causing considerable worldwide social and health alarm due to its association with ocular lesions and microcephaly in newborns, and Guillain–Barré syndrome (GBS) cases in adults. Nowadays, no licensed vaccines or antivirals are available against ZIKV, and thus, in this very short time, the scientific community has conducted enormous efforts to develop vaccines and antivirals. So that, different platforms (purified inactivated and live attenuated viruses, DNA and RNA nucleic acid based candidates, virus-like particles, subunit elements, and recombinant viruses) have been evaluated as vaccine candidates. Overall, these vaccines have shown the induction of vigorous humoral and cellular responses, the decrease of viremia and viral RNA levels in natural target organs, the prevention of vertical and sexual transmission, as well as that of ZIKV-associated malformations, and the protection of experimental animal models. Some of these vaccine candidates have already been assayed in clinical trials. Likewise, the search for antivirals have also been the focus of recent investigations, with dozens of compounds tested in cell culture and a few in animal models. Both direct acting antivirals (DAAs), directed to viral structural proteins and enzymes, and host acting antivirals (HAAs), directed to cellular factors affecting all steps of the viral life cycle (binding, entry, fusion, transcription, translation, replication, maturation, and egress), have been evaluated. It is expected that this huge collaborative effort will produce affordable and effective therapeutic and prophylactic tools to combat ZIKV and other related still unknown or nowadays neglected flaviviruses. Here, a comprehensive overview of the advances made in the development of therapeutic measures against ZIKV and the questions that still have to be faced are summarized.

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Discovery of Immunologically Inspired Small Molecules That Target the Viral Envelope Protein

Cited by 21 publications

References 34 publications

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

A Sensitive Yellow Fever Virus Entry Reporter Identifies Valosin-Containing Protein (VCP/p97) as an Essential Host Factor for Flavivirus Uncoating

Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors

Therapeutic Advances Against ZIKV: A Quick Response, a Long Way to Go

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