TY  - JOUR
AU  - HU Nan
AU  - SHIOTA Hiroshi
PY  - 2016
TI  - Emergence of resistance to carbocyclic oxetanocin G in herpes simplex virus type 1 and genetic analysis of resistant mutants
JF  - Acta Pharmacologica Sinica; Vol 25, No 7 (July 2004): Acta Pharmacologica Sinica
Y2  - 2016
KW  - 
N2  - AIM:  To elucidate the potentiality of emergence of drug-resistance to carbocyclic oxetanocin G (C.OXT-G), a new effective antiviral drug for herpetic keratitis during treatment and the mechanism of this drug resistance.  METHODS:  A C.OXT-G resistant strain (C.OXT-Gr) was established by serially propagating the herpes simplex virus (HSV) -1 in African green monkey kidney (VERO) cells in the presence of C.OXT-G. After the drug sensitivity assay and the thymidine kinase (TK) activity assay, the molecular basis for the drug resistance was studied using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and PCR direct sequencing technology.  RESULTS:  After the 10th passage in 10 microm C.OXT-G, the ED50 of the C.OXT-Gr was 17.08-fold greater than that of the original strain on the average and the TK activities of these resistant strains were extremely reduced. PCR-SSCP analysis on TK gene of the wild HSV-1 and the C.OXT-Gr showed altered migration patterns in part 3 and part 4, while PCR-SSCP analysis on DNA polymerase gene showed no difference among the viruses. Sequence analysis revealed a deletion of G at position of 430 that caused frameshift, resulting in premature termination in the TK gene.  CONCLUSION:  The drug resistance to C.OXT-G may appear during the treatment due to the deficiency of TK activity caused by a single mutation in the TK gene of HSV-1.
UR  - http://www.chinaphar.com/article/view/8292