title: Potent inhibition of enterovirus D68 and human rhinoviruses by dipeptidyl aldehydes and α-ketoamides.
abstract: Enterovirus D68 (EV-D68) is an emerging pathogen responsible for mild to severe respiratory infections that occur mostly in infants, children and teenagers. EV-D68, one of more than 100 non-polio enteroviruses, is acid-labile and biologically similar to human rhinoviruses (HRV) (originally classified as HRV87). However, there is no approved preventive or therapeutic measure against EV-D68, HRV, or other enteroviruses. In this study, we evaluated the antiviral activity of series of dipeptidyl compounds against EV-D68 and HRV strains, and demonstrated that several peptidyl aldehyde and α-ketoamide peptidyl compounds are potent inhibitors of EV-D68 and HRV strains with high in-vitro therapeutic indices (>1000). One of the α-ketoamide compounds is shown to have favorable pharmacokinetics profiles, including a favorable oral bioavailability in rats. Recent successful development of α-ketoamide protease inhibitors against hepatitis C virus suggests these compounds may have a high potential for further optimization and development against emerging EV-D68, as well as HRV.
authors.affiliation: Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA.
authors.forename: Yunjeong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS, USA.
authors.forename: Anushka C Galasiti
authors.initials: AC
authors.lastname: Kankanamalage
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS, USA.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Damalanka
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS, USA.
authors.forename: Pathum M
authors.initials: PM
authors.lastname: Weerawarna
authors.affiliation: Department of Chemistry, Wichita State University, Wichita, KS, USA. Electronic address: bill.groutas@wichita.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
authors.affiliation: Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA. Electronic address: kchang@vet.ksu.edu.
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D030016:Enterovirus D, Human / Q000187:drug effects*; D004769:Enterovirus Infections / Q000188:drug therapy* / Q000821:virology; D005260:Female; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D010850:Picornaviridae Infections / Q000188:drug therapy* / Q000821:virology; D017207:Rats, Sprague-Dawley; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000821:virology; D012229:Rhinovirus / Q000187:drug effects*
chemical_list: D000447:Aldehydes; D000577:Amides; D000998:Antiviral Agents; D004151:Dipeptides
keywords: Aldehyde and α-ketoamide peptidyl compounds; Antivirals; Enterovirus D68; Human rhinovirus