About: Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small-Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity

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About: Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small-Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity 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
title	Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small-Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity
Creator	Ahmed-Belkacem, Abdelhakim Ahnou, Nazim Baudesson, Camille Brillet, Rozenn Bruscella, Patrice Chazal, Maxime Donati, Flora Fourati, Slim Gelin, Muriel Guichou, Jean-François Jouvenet, Nolwenn Nevers, Quentin Pawlotsky, Jean-Michel Ruiz, Isaac Softic, Laurent
source	Medline; PMC
abstract	Although members of the Flaviviridae display high incidence, morbidity, and mortality rates, the development of specific antiviral drugs for each virus is unlikely. Cyclophilins, a family of host peptidyl-prolyl cis-trans isomerases (PPIases), play a pivotal role in the life cycles of many viruses and therefore represent an attractive target for broad-spectrum antiviral development. We report here the pangenotypic anti-hepatitis C virus (HCV) activity of a small-molecule cyclophilin inhibitor (SMCypI). Mechanistic and modeling studies revealed that the SMCypI bound to cyclophilin A in competition with cyclosporine (CsA), inhibited its PPIase activity, and disrupted the CypA-nonstructural protein 5A (NS5A) interaction. Resistance selection showed that the lead SMCypI hardly selected amino acid substitutions conferring low-level or no resistance in vitro. Interestingly, the SMCypI selected D320E and Y321H substitutions, located in domain II of the NS5A protein. These substitutions were previously associated with low-level resistance to cyclophilin inhibitors such as alisporivir. Finally, the SMCypI inhibited the replication of other members of the Flaviviridae family with higher 50% effective concentrations (EC(50)s) than for HCV. Thus, because of its chemical plasticity and simplicity of synthesis, our new family of SMCypIs represents a promising new class of drugs with the potential for broad-spectrum anti-Flaviviridae activity as well as an invaluable tool to explore the role of cyclophilins in viral life cycles.
has issue date	2018-06-26(xsd:dateTime)
bibo:doi	10.1128/aac.00126-18
bibo:pmid	29760125
has license	cc-by
sha1sum (hex)	1c60d93cd686bb14fac65510ad3de47cf8b9332c
schema:url	https://doi.org/10.1128/aac.00126-18
resource representing a document's title	Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small-Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity
has PubMed Central identifier	PMC6021681
has PubMed identifier	29760125
schema:publication	Antimicrob Agents Chemother
resource representing a document's body	covid:1c60d93cd686bb14fac65510ad3de47cf8b9332c#body_text
is schema:about of	named entity 'broad-spectrum' named entity 'promising' named entity 'cyclosporine' named entity 'selected' named entity 'domain' named entity 'family' named entity 'protein' named entity 'Potential' named entity 'Characterization' covid:arg/1c60d93cd686bb14fac65510ad3de47cf8b9332c named entity 'virus' named entity 'studies' named entity 'protein' named entity 'explore' named entity 'NS5A' named entity 'located' named entity 'acid' named entity 'resistance' named entity 'activity' named entity 'broad-spectrum' named entity 'inhibited' named entity 'family' named entity 'cyclophilin' named entity 'attractive' named entity 'Flaviviridae' named entity 'small-molecule' named entity 'PPIase' named entity 'NS5A' named entity 'HCV' named entity 'cyclosporine' named entity 'CsA' named entity 'effective' named entity 'tool' named entity 'CsA' named entity 'transfected' named entity 'Denmark' named entity 'small-molecule' named entity 'imidazole' named entity 'NS5B' named entity 'Plasmids' named entity 'synergistic' named entity 'coronaviruses' named entity 'Protein Data Bank' named entity 'Ralf Bartenschlager' named entity 'protein-protein interaction' named entity 'cell cultures' named entity 'DENV' named entity 'primers' named entity 'DENV' named entity 'Huh7' named entity 'rational design' named entity 'Viral replication' named entity 'antiviral' named entity 'antisense' named entity 'cyclophilins' named entity 'wild-type' named entity 'HCV' named entity 'imidazole' named entity 'CsA' named entity 'Ni-NTA' named entity 'RNA' named entity 'nitrilotriacetic acid' named entity 'PPIase' named entity 'viruses' named entity 'wild-type' named entity 'standard deviations' named entity 'CsA'

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