Mutations in the 2C region of poliovirus responsible for altered sensitivity to benzimidazole derivatives

Citation
H. Shimizu et al., Mutations in the 2C region of poliovirus responsible for altered sensitivity to benzimidazole derivatives, J VIROLOGY, 74(9), 2000, pp. 4146-4154
Citations number
76
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Microbiology
Journal title
JOURNAL OF VIROLOGY
ISSN journal
0022-538X → ACNP
Volume
74
Issue
9
Year of publication
2000
Pages
4146 - 4154
Database
ISI
SICI code
0022-538X(200005)74:9<4146:MIT2RO>2.0.ZU;2-6
Abstract
MRL-1237, [1-(4-fluorophenyl)-2-(4-imino-1,4-dihydropyridin-1-yl) methylben zimidazole hydrochloride], is a potent and selective inhibitor of the repli cation of enteroviruses. To reveal the target molecule of MRL-1237 in viral replication, we selected spontaneous MRL-1237-resistant poliovirus mutants . Of 15 MRL-1237-resistant mutants obtained, 14 were cross-resistant to gua nidine hydrochloride (mrgr), while 1 was susceptible (mrgs), Sequence analy sis of the 2C region revealed that the 14 mrgr mutants contained a single n ucleotide substitution that altered an amino acid residue from Phe-163 to T yr, The mrgs mutant, on the other hand, contained a substitution of Ile-120 to Val, Through the construction of a cDNA-derived mutant, we confirmed th at the single mutation at Phe-164 was really responsible for the reduced su sceptibility to MRL-1237. MRL-1237 inhibited poliovirus-specific RNA synthe sis in HeLa cells infected with a wild strain but not with an F164Y mutant. We furthermore examined the effect of mutations of the 2C region on the dr ug sensitivity of cDNA-derived guanidine-resistant and -dependent mutants. Two guanidine-resistant mutants were cross resistant to MRL-1237 but remain ed susceptible to another benzimidazole, enviroxime. Either MRL-1237 or gua nidine stimulated the viral replication of two guanidine-dependent mutants, but enviroxime did not. These results indicate that MRG1237, like guanidin e, targets the 2C protein of poliovirus for its antiviral effect.