title: Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity.
abstract: A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.
authors.affiliation: University of Maryland, Baltimore County, Department of Chemistry & Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Peters
authors.affiliation: Rega Institute, University of Leuven (KULeuven), Minderbroederstraat 10, Leuven BE-3000, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jochmans
authors.affiliation: Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Adriaan H
authors.initials: AH
authors.lastname: de Wilde
authors.affiliation: Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Clara C
authors.initials: CC
authors.lastname: Posthuma
authors.affiliation: Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Snijder
authors.affiliation: Rega Institute, University of Leuven (KULeuven), Minderbroederstraat 10, Leuven BE-3000, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: University of Maryland, Baltimore County, Department of Chemistry & Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: kseley@umbc.edu.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Seley-Radtke
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D017934:Coronavirus / Q000187:drug effects* / Q000502:physiology; D018352:Coronavirus Infections / Q000188:drug therapy*; D058957:Coronavirus NL63, Human / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D006801:Humans; D065207:Middle East Respiratory Syndrome Coronavirus / Q000187:drug effects / Q000502:physiology; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects / Q000502:physiology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D000212:Acyclovir
keywords: Acyclovir; Antiviral; Coronaviruses; Fleximers; MERS-CoV; Nucleosides; SARS