title: The thiazolobenzimidazole TBZE-029 inhibits enterovirus replication by targeting a short region immediately downstream from motif C in the nonstructural protein 2C.
abstract: TBZE-029 {1-(2,6-difluorophenyl)-6-trifluoromethyl-1H,3H-thiazolo[3,4-a]benzimidazole} is a novel selective inhibitor of the replication of several enteroviruses. We show that TBZE-029 exerts its antiviral activity through inhibition of viral RNA replication, without affecting polyprotein processing. To identify the viral target of TBZE-029, drug-resistant coxsackievirus B3 (CVB3) was selected. Genotyping of resistant clones led to the identification of three amino acid mutations in nonstructural protein 2C, clustered at amino acid positions 224, 227, and 229, immediately downstream of NTPase/helicase motif C. The mutations were reintroduced, either alone or combined, into an infectious full-length CVB3 clone. In particular the mutations at positions 227 and 229 proved essential for the altered sensitivity of CVB3 to TBZE-029. Resistant virus exhibited cross-resistance to the earlier-reported antienterovirus agents targeting 2C, namely, guanidine hydrochloride, HBB [2-(alpha-hydroxybenzyl)-benzimidazole], and MRL-1237 {1-(4-fluorophenyl)-2-[(4-imino-1,4-dihydropyridin-1-yl)methyl]benzimidazole hydrochloride}. The ATPase activity of 2C, however, remained unaltered in the presence of TBZE-029.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Armando M
authors.initials: AM
authors.lastname: De Palma
authors.forename: Ward
authors.initials: W
authors.lastname: Heggermont
authors.forename: Kjerstin
authors.initials: K
authors.lastname: Lanke
authors.forename: Bruno
authors.initials: B
authors.lastname: Coutard
authors.forename: Mirko
authors.initials: M
authors.lastname: Bergmann
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Monforte
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Alba
authors.initials: A
authors.lastname: Chimirri
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pürstinger
authors.forename: Jacques
authors.initials: J
authors.lastname: Rohayem
authors.forename: Frank
authors.initials: F
authors.lastname: van Kuppeveld
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D020816:Amino Acid Motifs; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral / Q000235:genetics; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000235:genetics; D019791:Guanidine / Q000494:pharmacology; D015394:Molecular Structure; D020125:Mutation, Missense; D011725:Pyridines / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D013844:Thiazoles / Q000494:pharmacology*; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D002352:Carrier Proteins; C407906:MRL 1237; D011725:Pyridines; D012367:RNA, Viral; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C073244:1-(2',6'-difluorophenyl)-1H,3H-thiazolo(3,4-a)benzimidazole; C021033:HBBPC; C076023:2C protein, viral; D000251:Adenosine Triphosphatases; D019791:Guanidine