About: An E460D substitution in the NS5 protein of tick-borne encephalitis virus confers resistance to the inhibitor Galidesivir (BCX4430) and also attenuates the virus for mice

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About: An E460D substitution in the NS5 protein of tick-borne encephalitis virus confers resistance to the inhibitor Galidesivir (BCX4430) and also attenuates the virus for mice Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	An E460D substitution in the NS5 protein of tick-borne encephalitis virus confers resistance to the inhibitor Galidesivir (BCX4430) and also attenuates the virus for mice
Creator	De Clercq, Erik Gould, Ernest Nougairède, Antoine Haviernik, Jan Ruzek, Daniel Darina, De 5 Lamballerie, Xavier Driouich, Jean-Sélim Eyer, Ludek Uhlířová, Marie Valdés, James
Source	BioRxiv
abstract	The adenosine analogue Galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, has entered a Phase 1 clinical safety and pharmacokinetics study in healthy subjects and is under clinical development for treatment of Ebola virus infection. Moreover, Galidesivir also inhibits the reproduction of tick-borne encephalitis virus (TBEV) and numerous other medically important flaviviruses. Until now, studies of this antiviral agent have not yielded resistant viruses. Here, we demonstrate that an E460D substitution, in the active site of TBEV RNA-dependent-RNA-polymerase (RdRp), confers resistance to Galidesivir in cell culture. Stochastic molecular simulations indicate that the steric freedom caused by the E460D substitution increases close electrostatic interactions between the inhibitor and the interrogation residue of the TBEV RdRp motif F, resulting in rejection of the analogue as an incorrect/modified nucleotide. Galidesivir-resistant TBEV exhibited no cross-resistance to structurally different antiviral nucleoside analogues, such as 7-deaza-2’-C-methyladenosine, 2’-C-methyladenosine and 4’-azido-aracytidine. Although, the E460D substitution led only to a subtle decrease in viral fitness in cell culture, Galidesivir-resistant TBEV was highly attenuated in vivo, with 100% survival rate and no clinical signs observed in infected mice. Our results contribute to understanding the molecular basis of Galidesivir antiviral activity, flavivirus resistance to nucleoside inhibitors and the potential contribution of viral RdRp to flavivirus neurovirulence. Importance Tick-borne encephalitis virus (TBEV) is a pathogen that causes severe human neuroinfections in large areas of Europe and Asia and for which there is currently no specific therapy. We have previously found that Galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, which is under clinical development for treatment of Ebola virus infection, has a strong antiviral effect against TBEV. For any antiviral drug, it is important to generate drug-resistant mutants to understand how the drug works. Here, we produced TBEV mutants resistant to Galidesivir and found that the resistance is caused by a single amino acid substitution in an active site of the viral RNA-dependent RNA polymerase, an enzyme which is crucial for replication of viral RNA genome. Although, this substitution led only to a subtle decrease in viral fitness in cell culture, Galidesivir-resistant TBEV was highly attenuated in a mouse model. Our results contribute to understanding the molecular basis of Galidesivir antiviral activity.
has issue date	2019-02-28(xsd:dateTime)
bibo:doi	10.1101/563544
has license	biorxiv
sha1sum (hex)	0ae0e227f20960cc18b33946a7c92969dfac79a2
schema:url	https://doi.org/10.1101/563544
resource representing a document's title	An E460D substitution in the NS5 protein of tick-borne encephalitis virus confers resistance to the inhibitor Galidesivir (BCX4430) and also attenuates the virus for mice
schema:publication	bioRxiv
resource representing a document's body	covid:0ae0e227f20960cc18b33946a7c92969dfac79a2#body_text
is schema:about of	named entity 'Phase' named entity 'electrostatic interactions' named entity 'studies' named entity 'subjects' named entity 'infected' named entity 'medically' named entity 'broad-spectrum' named entity 'analogue' named entity 'steric' named entity 'survival rate' named entity 'inhibitor' named entity 'virus' named entity 'OBSERVED' named entity 'SURVIVAL RATE' named entity 'Although' named entity 'simulations' named entity 'led' named entity 'resistance' named entity 'RdRp' named entity 'flaviviruses' named entity 'motif' named entity 'cell' named entity 'nucleoside' named entity 'antiviral' named entity 'TBEV' named entity 'Galidesivir' named entity 'adenosine' named entity 'survival rate' named entity 'cross-resistance' named entity 'Stochastic' named entity 'motif' named entity 'nucleotide' named entity 'antiviral agent' named entity 'clinical development' named entity 'cell culture' named entity 'RNA-polymerase' named entity 'clinical signs' named entity 'TBEV' named entity 'TBEV' named entity 'tick-borne encephalitis virus' named entity 'virus' named entity 'BCX4430' named entity 'NS5 protein' named entity 'clinical development' named entity 'reverse genetics' named entity 'motif' named entity 'conformation' named entity 'wild type' named entity 'San Diego' named entity 'motif' named entity 'Galidesivir' named entity 'transfected' named entity 'Asp' named entity 'virus infection' named entity 'primers' named entity 'wild-type' named entity 'wild-type virus' named entity 'genotype' named entity 'aspartic acid' named entity 'wild-type virus' named entity 'recombinant' named entity 'Glu' named entity 'TBEV' named entity 'whole-genome sequencing' named entity 'RdRp' named entity 'kcal' named entity 'active site' named entity 'cofactors' named entity 'stochastic' named entity 'EC50' named entity 'ligand binding' named entity 'Galidesivir' named entity 'viral titers' named entity 'RdRp'

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