Incorporation and metabolism of 2′-fluoro-5-substituted arabinosyl pyrimidines and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells Journal Article
| Authors: | Kong, X. B.; Scheck, A. C.; Price, R. W.; Vidal, P. M.; Fanucchi, M. P.; Watanabe, K. A.; Fox, J. J.; Chou, T. C. |
| Article Title: | Incorporation and metabolism of 2′-fluoro-5-substituted arabinosyl pyrimidines and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells |
| Abstract: | The incorporation and metabolism of 2′-fluoro-5-substituted arabinosyl pyrimidine analogs, and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells were studied by HPLC and CsCl isopycnic density gradient analysis of isolated DNAs. The amounts of radiolabeled analogs incorporated as parent compound following 10 μM exposure for 4 h were 10-fold higher in HSV-1-infected vs mock-infected cells for 2′-fluoro-5-difluoromethyl-Ara-U (F2FMAU); 4.3-fold higher for 5-ethyl deoxyuridine (EdU); 2.6-fold higher for 2′-fluoro-5-methyl-Ara-U (FMAU) and 1.7-fold higher for dThd. For 2′-fluoro-5-ethyl-Ara-U (FEAU), 3.0 pmole of unchanged moiety was incorporated per 106 HSV-1-infected cells but no incorporation was detected in mock-infected cells. HPLC profiles showed that the percentages of radiolabeled analogs incorporated as parent compound in the DNA extracted from HSV-1-infected cells were 31.0% for F2FMAU, 99.6% for EdU, 83.5% for FEAU and 98.3% for FMAU; from mock-infected cells, they were 63.6% for F2FMAU, 96.7% for EdU, 97.3% for FMAU and no incorporation into DNA for FEAU was detected. CsCl density gradient analyses of isolated DNA showed that viral DNA synthesis was inhibited 98% by 10 μM FEAU, 92% by 10 μM F2FMAU, 90% by 2 μM FMAU and 80% by 50 μM EdU, whereas cellular DNA synthesis was inhibited by 53, 44, 61, 66 and 54%, respectively. We conclude that: (a) FEAU incorporation into host-cell DNA was not detectable but FEAU was selectively incorporated into HSV-infected cells; (b) FMAU and FEAU were metabolically stable; however, F2FMAU was extensively metabolized; (c) FEAU and F2FMAU were among the most selective inhibitors of HSV-1 DNA synthesis while allowing cellular DNA synthesis to continue. © 1988. |
| Keywords: | unclassified drug; nonhuman; dna synthesis; animal; metabolism; cell culture; simplexvirus; dna, viral; molecular structure; high performance liquid chromatography; chromatography, high pressure liquid; herpes simplex virus 1; herpes simplex virus; thymidine; vero cells; antiviral agents; selective inhibition; virus inhibition; arabinonucleosides; pyrimidine nucleosides; priority journal; edoxudine; incorporation; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; 2′-fluoro-5-substituted-ara-pyrimidine; 2' deoxy 2' fluorocytarabine derivative; 2' fluoro 2' deoxyuracil arabinoside derivative; centrifugation, isopycnic |
| Journal Title: | Antiviral Research |
| Volume: | 10 |
| Issue: | 4-5 |
| ISSN: | 0166-3542 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 1988-12-01 |
| Start Page: | 153 |
| End Page: | 166 |
| Language: | English |
| DOI: | 10.1016/0166-3542(88)90028-9 |
| PUBMED: | 2852483 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 6 August 2020 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work