Inhibition of Lassa virus and Ebola virus infection in host cells treated with the kinase inhibitors genistein and tyrphostin

Kolokoltsov, Andrey A.; Adhikary, Shramika; Garver, Jennifer; Johnson, Lela; Davey, Robert A.; Vela, Eric M.

doi:10.1007/s00705-011-1115-8

Cited by 44 publications

(30 citation statements)

References 28 publications

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“…These results would suggest that in BHK-21 cells JUNV uses a different receptor that is internalized by an EIPA-sensitive endocytic pathway that may involve activation of the receptor tyrosine kinases TIM or TAM, or both, as has been proposed for several other enveloped viruses (56). Accordingly, broad-range protein kinase inhibitors like staurosporine and genistein are able to inhibit viral cell entry mediated by macropinocytois (84), and genistein treatment was shown to inhibit both LASV (85) and Pichinde virus (86) infections. NHE3 was also identified in the same siRNA screen as a host cell factor required for efficient multiplication of VSV in HeLa cells (22).…”

Section: Discussionmentioning

confidence: 72%

Sodium Hydrogen Exchangers Contribute to Arenavirus Cell Entry

Iwasaki

Ngo

Torre

2014

J Virol

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Section: Discussionmentioning

confidence: 72%

Sodium Hydrogen Exchangers Contribute to Arenavirus Cell Entry

Iwasaki

Ngo

Torre

2014

J Virol

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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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“…Although the molecular target is not known, CMLDBU3402 (25) exhibited broad spectrum activity against a number of non-segmented single RNA viruses including EBOV and inhibited RNA transcription in EBOV (Filone et al, 2013). Other compounds, which were shown to have activity against Ebola virus include antioxidants , selective estrogen receptor modulators (Johansen et al, 2013), cell cycle inhibitors and kinase inhibitors (Kolokoltsov et al, 2012).…”

Section: Other Potential Targets and Miscellaneous Compounds With Actmentioning

confidence: 97%

Ebola Virus Potential Drug Targets and Prospects for Small Molecule Drug Discovery

Assefa¹

2014

j pharmaceut sci pharmacol

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Ebola virus is an enveloped non-segmented negative-sense single strand RNA virus. It causes a fetal severe hemorrhagic fever or Ebola virus disease with very low recovery rate. Since its occurrence in the 1970s in northern Zaire and south Sudan, there has been numerous outbreaks, all of which in the tropical regions of Africa. The latest and the largest one and still ongoing was first identified in March 2014. Although the outbreaks were in the tropical Africa, other countries have been affected because of the travel and highly contagious nature of the Ebola virus disease. In addition, there is a potential for the virus to be used as a bioterrorism weapon. Therefore, Ebola virus disease poses a global health threat. Due to the frequent outbreaks, highly contagious and fast replication of the virus, high mortality rate from Ebola virus disease, and the potential of the virus for being used as bioweapon, there is an urgent need for the discovery of Ebola virus disease therapeutic agents. Numerous compounds have been found to inhibit Ebola virus infection in vitro and in animal models, and several viral and host proteins have been identified as potential targets. Among these, the viral RNA-dependent RNA polymerase inhibitors, Viral entry inhibitors, the host S-adenosylhomocysteine hydrolase inhibitors are the most promising. Due the fast replication and spread of the virus, a combination of the RNA polymerase, entry and S-adenosylhomocysteine hydrolase inhibitors would be very effective in controlling the disease and decreasing mortality.

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Inhibition of Lassa virus and Ebola virus infection in host cells treated with the kinase inhibitors genistein and tyrphostin

Cited by 44 publications

References 28 publications

Sodium Hydrogen Exchangers Contribute to Arenavirus Cell Entry

Sodium Hydrogen Exchangers Contribute to Arenavirus Cell Entry

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

Ebola Virus Potential Drug Targets and Prospects for Small Molecule Drug Discovery

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