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Titolo:
Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071.
Autore:
Tai, CY; Escarpe, PA; Sidwell, RW; Williams, MA; Lew, W; Wu, HW; Kim, CU; Mendel, DB;
Indirizzi:
Gilead Sci Inc, Res Virol, Foster City, CA 94404 USA Gilead Sci Inc Foster City CA USA 94404 Virol, Foster City, CA 94404 USA Gilead Sci Inc, Med Chem, Foster City, CA 94404 USA Gilead Sci Inc FosterCity CA USA 94404 d Chem, Foster City, CA 94404 USA Utah State Univ, Inst Antiviral Res, Logan, UT 84322 USA Utah State Univ Logan UT USA 84322 nst Antiviral Res, Logan, UT 84322 USA
Titolo Testata:
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
fascicolo: 12, volume: 42, anno: 1998,
pagine: 3234 - 3241
SICI:
0066-4804(199812)42:12<3234:COHIVV>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
GG167 4-GUANIDINO-2,4-DIDEOXY-2,3-DEHYDRO-N-ACETYLNEURAMINIC ACID; SIALIC-ACID; IN-VITRO; DECREASED SENSITIVITY; ACTIVE-SITE; 4-GUANIDINO-NEU5AC2EN; REPLICATION; MUTANTS; GROWTH; GENERATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Mendel, DB Gilead Sci Inc, Res Virol, 333 Lakeside Dr, Foster City, CA 94404 USA Gilead Sci Inc 333 Lakeside Dr Foster City CA USA 94404 404 USA
Citazione:
C.Y. Tai et al., "Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071.", ANTIM AG CH, 42(12), 1998, pp. 3234-3241

Abstract

An oral prodrug of GS 4071, a potent and selective inhibitor of influenza neuraminidases, is currently under clinical development for the treatment and prophylaxis of influenza virus infections in humans. To investigate the potential development of resistance during the clinical use of this compound, variants of the human influenza A/Victoria/3/75 (H3N2) virus with reduced susceptibility to the neuraminidase inhibitor GS 4071 were selected in vitro by passaging the virus in MDCK cells in the presence of inhibitor. After eight passages, variants containing two amino acid substitutions in the hemagglutinin (A28T in HA1 and R124M in HA2) but no changes in the neuraminidase were isolated. These variants exhibited a 10-fold reduction in susceptibility to GS 4071 and zanamivir (GG167) in an in vitro plaque reduction assay. After 12 passages, a second variant containing these hemagglutinin mutations and a Lys substitution for the conserved Arg292 of the neuraminidasewas isolated. The mutant neuraminidase enzyme exhibited high-level (30,000-fold) resistance to GS 4071, but only moderate (30-fold) resistance to zanamivir and 4-amino-Neu5Ac2en, the amino analog of zanamivir. The mutant enzyme had weaker affinity for the fluorogenic substrate 2'-(4-methylumbelliferyl)-alpha-D-N-acetylneuraminic acid and lower enzymatic activity compared to the wild-type enzyme. The viral variant containing the mutant neuraminidase did not replicate as well as the wild-type virus in culture and was 10,000-fold less infectious than the wild-type virus in a mouse model. These results suggest that although the R292K neuraminidase mutation confers high-level resistance to GS 4071 in vitro, its effect on viral virulence is likely to render this mutation of limited clinical significance.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 09:11:23