An antiviral disulfide compound blocks interaction between arenavirus Z protein and cellular promyelocytic leukemia protein

Topisirović, Ivan; Djavani, Mahmoud; Borden, Katherine L. B.; Damonte, Elsa B.; Salvato, María S.

doi:10.1016/j.bbrc.2010.02.040

Cited by 22 publications

(19 citation statements)

References 39 publications

(37 reference statements)

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“…To our knowledge, small molecules targeting the viral PPxYhost Nedd4 interaction have not been reported; however, a number of previous studies have reported on antivirals targeting virushost interactions and/or budding of filoviruses, arenaviruses, rhabdoviruses, and others (7,9,12,31,(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)(81). Host Tsg101 and its recruitment by viral PTAP type L domains of RNA viruses have been targeted for the development of antivirals in a number of recent studies (7,9,31,39,71,(82)(83)(84)(85)(86)(87)(88).…”

Section: Discussionmentioning

confidence: 99%

Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses

Han

Liu

et al. 2014

J Virol

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Budding of filoviruses, arenaviruses, and rhabdoviruses is facilitated by subversion of host proteins, such as Nedd4 E3 ubiquitin ligase, by viral PPxY late (L) budding domains expressed within the matrix proteins of these RNA viruses. As L domains are important for budding and are highly conserved in a wide array of RNA viruses, they represent potential broad-spectrum targets for the development of antiviral drugs. To identify potential competitive blockers, we used the known Nedd4 WW domain-PPxY interaction interface as the basis of an in silico screen. Using PPxY-dependent budding of Marburg (MARV) VP40 virus-like particles (VLPs) as our model system, we identified small-molecule hit 1 that inhibited Nedd4-PPxY interaction and PPxY-dependent budding. This lead candidate was subsequently improved with additional structure-activity relationship (SAR) analog testing which enhanced antibudding activity into the nanomolar range. Current lead compounds 4 and 5 exhibit on-target effects by specifically blocking the MARV VP40 PPxY-host Nedd4 interaction and subsequent PPxY-dependent egress of MARV VP40 VLPs. In addition, lead compounds 4 and 5 exhibited antibudding activity against Ebola and Lassa fever VLPs, as well as vesicular stomatitis and rabies viruses (VSV and RABV, respectively). These data provide target validation and suggest that inhibition of the PPxY-Nedd4 interaction can serve as the basis for the development of a novel class of broad-spectrum, host-oriented antivirals targeting viruses that depend on a functional PPxY L domain for efficient egress. IMPORTANCEThere is an urgent and unmet need for the development of safe and effective therapeutics against biodefense and high-priority pathogens, including filoviruses (Ebola and Marburg) and arenaviruses (e.g., Lassa and Junin) which cause severe hemorrhagic fever syndromes with high mortality rates. We along with others have established that efficient budding of filoviruses, arenaviruses, and other viruses is critically dependent on the subversion of host proteins. As disruption of virus budding would prevent virus dissemination, identification of small-molecule compounds that block these critical viral-host interactions should effectively block disease progression and transmission. Our findings provide validation for targeting these virus-host interactions as we have identified lead inhibitors with broad-spectrum antiviral activity. In addition, such inhibitors might prove useful for newly emerging RNA viruses for which no therapeutics would be available.

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Section: Discussionmentioning

confidence: 99%

Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses

Han

Liu

et al. 2014

J Virol

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“…JUNV is endemic in regions of Argentina and West Africa and is the cause of severe episodes of hemorrhagic fever with high mortality rates. The search for effective therapeutics to treat arenavirus infections, particularly those caused by Junin and Lassa viruses, has been an active area of research for many years (8,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). More recent efforts in the field of antiviral therapeutics for emerging RNA viruses have focused on identifying host factors or virus-host interactions, rather than solely viral proteins, as targets for novel antivirals (6, 8-13, 39, 40, 43, 44).…”

Section: Discussionmentioning

confidence: 99%

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

Han

Liu

et al. 2014

J Virol

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IMPORTANCE There are currently no FDA-approved vaccines or therapeutics to prevent or treat Argentine hemorrhagic fever (AHF). The causative agent of AHF is Junin virus (JUNV); a New World arenavirus classified as an NIAID/CDC category A priority pathogen.Here, we describe a prototype therapeutic that blocks budding of JUNV and has the potential to function as a broad-spectrum antiviral drug. J unin virus (JUNV) is a New World arenavirus endemic in Argentina that causes severe Argentine hemorrhagic fever and significant mortality in humans (1). The virus is present in excreta from infected rodents and is typically spread to humans via aerosolization (1). JUNV is important because it is a biosafety level 4 pathogen with potential use as a bioterror agent, for which there are no U.S. Food and Drug Administration (FDA)-approved vaccines or therapeutics. JUNV is an enveloped, bisegmented negative-sense RNA virus that encodes four proteins: surface glycoprotein precursor (GPC), RNA polymerase (L), nucleoprotein (NP), and small RING finger matrix protein (Z). The Z protein of arenaviruses plays a key role in promoting virus egress and spread and is capable of budding independently from mammalian cells in the form of virus-like particles (VLPs) (2-6). Efficient separation of arenavirus Z VLPs from the plasma membrane is promoted by viral L domains within the Z protein (for a review, see reference 7). L domains function by recruiting host proteins that facilitate efficient virus-cell separation ("pinching-off") (7). JUNV Z protein contains a single PTAP type L domain which interacts with host Tsg101, a component of the endosomal sorting complexes required for transport (ESCRT) machinery (5-7). L-domain-mediated recruitment of host proteins by virus represents a potential target for the development of novel antiviral inhibitors to disrupt virus egress from infected cells to reduce virus dissemination and disease progression (3,6,(8)(9)(10)(11)(12)(13).Based upon the known nuclear magnetic resonance structure of the Tsg101-PTAP interaction site, we conducted an in silico screen for competitive binding inhibitors. We identified several compounds, and the most potent (compound 0013) blocks both Z VLP and live JUNV egress at nanomolar concentrations. Moreover, compound 0013 specifically blocks PTAP-Tsg101 interactions. Intriguingly, since L-domain-containing matrix proteins are generally required for efficient virus-cell separation of emerging RNA viruses (filoviruses, arenaviruses, henipaviruses, rhabdoviruses, paramyxoviruses, and retroviruses), we speculate that inhibitors of this virus-host interaction could represent broadspectrum antiviral drugs against a range of enveloped RNA viruses. MATERIALS AND METHODSCell lines, virus, and antibodies. VeroE6 and HEK293T cells were grown in Dulbecco modified Eagle medium supplemented with 10% fetal calf serum. The Candid-1 vaccine strain of JUNV was kindly provided by Robert B. Tesh (University of Texas Medical Branch, Galveston, TX) via

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“…In the case of LCMV, the compound was found to induce unfolding and oligomerization of Z to high-molecular-mass aggregates without affecting cellular RING-containing proteins such as PML 179 . However, NSC20625 did suppress LCMV Z-mediated PML nuclear bodies disruption, most likely by disrupting the Z-PML interaction 180 .…”

Section: Bodymentioning

confidence: 84%

Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses

Radoshitzky

Kuhn

Kok-Mercado

et al. 2012

Expert Opinion on Drug Discovery

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Introduction Seven arenaviruses cause viral hemorrhagic fever in humans: the Old World arenaviruses Lassa and Lujo, and the New World Clade B arenaviruses Machupo (MACV), Junín (JUNV), Guanarito (GTOV), Sabiá (SABV), and Chapare (CHPV). All of these viruses are Risk Group 4 biosafety pathogens. MACV causes human disease outbreak with high case-fatality rates. To date, at least 1,200 cases with ≈200 fatalities have been recorded 1, 2. Areas covered This review summarizes available systems and technologies for the identification of antivirals against MACV, animal models for in vivo evaluation of novel inhibitors, present treatment of arenaviral diseases, overview of efficacious small molecules and other therapeutics reported to date, and strategies to identify novel inhibitors for anti-arenaviral therapy. Expert opinion New high-throughput approaches to quantitate infection rates of areaviruses, as well as viruses modified to carry reporter genes, will accelerate compound screens and drug discovery efforts. RNAi, gene expression profiling and proteomics studies will identify host targets for therapeutic intervention. New discoveries in the cell entry mechanism of MACV and other arenaviruses as well as extensive structural studies of arenaviral L and NP could facilitate the rational design of antivirals effective against all pathogenic New World arenaviruses.

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An antiviral disulfide compound blocks interaction between arenavirus Z protein and cellular promyelocytic leukemia protein

Cited by 22 publications

References 39 publications

Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses

Small-Molecule Probes Targeting the Viral PPxY-Host Nedd4 Interface Block Egress of a Broad Range of RNA Viruses

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses

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