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  • ArenaviridaeendonucleasesLymphocytic choriomeningitis virusLCMVdiketo acidscompound optimizationmetal chelation  (1)
  • Asellus aquaticus  (1)
  • International Union of Crystallography (IUCr)  (1)
  • Springer  (1)
  • American Institute of Physics (AIP)
  • Taylor & Francis
  • 2015-2019  (2)
  • 1950-1954
  • 2018  (2)
  • 1
    Publication Date: 2018-02-23
    Description: The Arenaviridae family, together with the Bunyaviridae and Orthomyxoviridae families, is one of the three negative-stranded RNA viral families that encode an endonuclease in their genome. The endonuclease domain is at the N-terminus of the L protein, a multifunctional protein that includes the RNA-dependent RNA polymerase. The synthesis of mRNA in arenaviruses is a process that is primed by capped nucleotides that are `stolen' from the cellular mRNA by the endonuclease domain in cooperation with other domains of the L protein. This molecular mechanism has been demonstrated previously for the endonuclease of the prototype Lymphocytic choriomeningitis virus (LCMV). However, the mode of action of this enzyme is not fully understood as the original structure did not contain catalytic metal ions. The pivotal role played by the cap-snatching process in the life cycle of the virus and the highly conserved nature of the endonuclease domain make it a target of choice for the development of novel antiviral therapies. Here, the binding affinities of two diketo-acid (DKA) compounds (DPBA and L-742,001) for the endonuclease domain of LCMV were evaluated using biophysical methods. X-ray structures of the LCMV endonuclease domain with catalytic ions in complex with these two compounds were determined, and their efficacies were assessed in an in vitro endonuclease-activity assay. Based on these data and computational simulation, two new DKAs were synthesized. The LCMV endonuclease domain exhibits a good affinity for these DKAs, making them a good starting point for the design of arenavirus endonuclease inhibitors. In addition to providing the first example of an X-ray structure of an arenavirus endonuclease incorporating a ligand, this study provides a proof of concept that the design of optimized inhibitors against the arenavirus endonuclease is possible.
    Keywords: ArenaviridaeendonucleasesLymphocytic choriomeningitis virusLCMVdiketo acidscompound optimizationmetal chelation
    Electronic ISSN: 2052-2525
    Topics: Geosciences , Physics
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  • 2
    Publication Date: 2022-05-26
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Aquatic Sciences 80 (2018): 44, doi:10.1007/s00027-018-0594-z.
    Description: Complex natural systems are affected by multiple anthropogenic stressors, and therefore indirect effects within food webs are increasingly investigated. In this context, dead organic matter (OM) or detritus provides a food source sustaining detrital food webs that recycle the retained energy through microbial decomposition and invertebrate consumption. In aquatic environments, poorly water-soluble contaminants, including nanoparticles (NPs), quickly adsorb onto OM potentially modifying OM-associated microbial communities. Since invertebrates often depend on microbial conditioning to enhance OM quality, adverse effects on OM-associated microbial communities could potentially affect invertebrate performances. Therefore, this study assessed the effect of environmentally relevant concentrations of the model emerging contaminant, silver nanoparticles (AgNPs), on OM-associated microorganisms and subsequent indirect effects on growth of the invertebrate Asellus aquaticus. At low concentrations (0.8 ug/L), AgNPs inhibited activity and altered metabolic diversity of the OM-associated microbial community. This was observed to coincide with a negative effect on the growth of A. aquaticus due to antimicrobial properties, as a decreased growth was observed when offered AgNP-contaminated OM. When A. aquaticus were offered sterile OM in the absence of AgNPs, invertebrate growth was observed to be strongly retarded, illustrating the importance of microorganisms in the diet of this aquatic invertebrate. This outcome thus hints that environmentally relevant concentrations of AgNPs can indirectly affect the growth of aquatic invertebrates by affecting OM-associated microbial communities, and hence that microorganisms are an essential link in understanding bottom-up directed effects of chemical stressors in food webs.
    Description: The Chinese Scholarship Council (CSC) is gratefully acknowledged for its financial support to Yujia Zhai [201506510003]. Martina G. Vijver is funded by NWO-VIDI [project number 864.13.010].
    Keywords: Asellus aquaticus ; Food web ; Freshwater biofilms ; Decomposition and consumption ; Silver nanoparticles ; Ecosystem functioning
    Repository Name: Woods Hole Open Access Server
    Type: Article
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