title: Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds.
abstract: Compounds were evaluated for antiviral activity in rhabdomyosarcoma (RD) cells against a recent 2014 clinical isolate of enterovirus D68 (EV-D68), a 1962 strain of EV-68D, rhinovirus 87 (RV-87, serologically the same as EV-D68), and enterovirus 71 (EV-71). Test substances included known-active antipicornavirus agents (enviroxime, guanidine HCl, pirodavir, pleconaril, and rupintrivir), nucleobase/nucleoside analogs (3-deazaguanine and ribavirin), and three novel epidithiodiketopiperazines (KCN-2,2'-epi-19, KCN-19, and KCN-21). Of these, rupintrivir was the most potent, with 50% inhibition of viral cytopathic effect (EC50) and 90% inhibition (EC90) of virus yield at 0.0022-0.0053 μM against EV-D68. Enviroxime, pleconaril and the KCN compounds showed efficacy at 0.01-0.3 μM; 3-deazaguanine and pirodavir inhibited EV-D68 at 7-13 μM, and guanidine HCl and ribavirin were inhibitory at 80-135 μM. Pirodavir was active against EV-71 (EC50 of 0.78 μM) but not against RV-87 or EV-D68, and all other compounds were less effective against EV-71 than against RV-87 and EV-D68. The most promising compound inhibiting both virus infections at low concentrations was rupintrivir. Antiviral activity was confirmed for the ten compounds in virus yield reduction (VYR) assays in RD cells, and for enviroxime, guanidine HCl, and pirodavir by cytopathic effect (CPE) assays in A549, HeLa-Ohio-1, and RD cells. These studies may serve as a basis for further pre-clinical discovery of anti-enterovirus inhibitors. Furthermore, the antiviral profiles and growth characteristics observed herein support the assertion that EV-D68 should be classified together with RV-87.
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: Evans
authors.affiliation: The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
authors.forename: E Bart
authors.initials: EB
authors.lastname: Tarbet
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA. Electronic address: craig.day@usu.edu.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Day
mesh_terms: D000072283:A549 Cells; D000963:Antimetabolites / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000254:growth & development; D030016:Enterovirus D, Human / Q000187:drug effects* / Q000254:growth & development; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D010069:Oxadiazoles / Q000494:pharmacology; D010080:Oxazoles; D010091:Oximes; D010849:Picornaviridae / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D012208:Rhabdomyosarcoma; D012229:Rhinovirus / Q000187:drug effects* / Q000254:growth & development; D012254:Ribavirin / Q000494:pharmacology; D013449:Sulfonamides
chemical_list: D000963:Antimetabolites; D000998:Antiviral Agents; D001562:Benzimidazoles; D010069:Oxadiazoles; D010080:Oxazoles; D010091:Oximes; D010879:Piperazines; D010880:Piperidines; D011724:Pyridazines; D013449:Sulfonamides; C583099:epidithiodioxopiperazine; D012254:Ribavirin; D006147:Guanine; C010567:3-deazaguanine; C115201:pleconaril; C074589:pirodavir; C021595:viroxime
keywords: Antiviral; Enterovirus 71; Enterovirus D68; Picornavirus; Rhinovirus 87