title: Discovery, synthesis, and biological evaluation of a novel group of selective inhibitors of filoviral entry.
abstract: Herein, we report the development of an antifiloviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC(50) of 30 μM. To analyze functional group requirements for efficacy, a structure-activity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using "click" chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent antiviral agents with IC(50) values ranging to 2.5 μM. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.
authors.affiliation: Department of Chemistry, University of Illinois, 845 West Taylor Street, Chicago, IL 60607, USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Yermolina
authors.forename: Jizhen
authors.initials: J
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Caffrey
authors.forename: Lijun L
authors.initials: LL
authors.lastname: Rong
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Wardrop
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D057930:Click Chemistry; D029043:Ebolavirus / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D029024:Marburgvirus / Q000187:drug effects* / Q000472:pathogenicity; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014759:Viral Envelope Proteins / Q000502:physiology; D014773:Virology / Q000379:methods; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007555:Isoxazoles; D054852:Small Molecule Libraries; D014230:Triazoles; D014759:Viral Envelope Proteins