Activity of trifluorothymidine against cytomegalovirus

Wingard, John R.; Stuart, R K; Saral, Rein; Burns, William H.

doi:10.1128/aac.20.3.286

Cited by 30 publications

(8 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, since other 5-halo-ara-Us cannot inhibit thymidylate synthetase, their antiviral activity against HCMV may be weaker than that of ara-FU. Wingard et al (18) reported that trifluorothymidine is active against HCMV replication. They suggested that the compound inhibits thymidylate synthetase and viral DNA polymerase after phosphorylation by cellular thymidine kinase to its monophosphate and triphosphate forms, respectively.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil

Saneyoshi¹,

Nakayama²,

Nishiyama³

et al. 1985

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Four kinds of l-p-D-arabinofuranosyl-5-halogenouracil were examined for inhibition of human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) replication. 1-j3-DArabinofuraaosyl-5-fluorouracil (ara-FU) was the most effective against HCMV, whereas l-1-D-arabinofuranosyl-5-bromouracil was the most effective against HSV-1 and HSV-2. The mechanism of action of ara-FU on HCMV replication was also studied. The dTTP pool size in human embryonic fibroblasts was increased 33-fold by HCMV infection. However, treatment with ara-FU decreased the size of the dTTP pool by approximately 50%. On the other hand, l-1B-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate inhibited ICMV DNA polymerase activity competitively with dTTP. These results suggest that ara-FU acts as a bifunctional inhibitor of HCMV replication. Ara-FU is phosphorylated by cellular thymidine kinase to l-(B-D-arabinofuranosyl-5-fluorouracil-5'-monopbosphate, which inhibits cellular thymidylate synthetase, which in turn decreases the dTTP pool size in infected cells. As the dTTP pool size is reduced, inhibition of viral DNA polymerase by l-(3-D-arabinofuranosyl-5-fluorouracil-5'-triphosphate becomes more efficient.A number of compounds exhibit a highly selective inhibitory effect against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) (2). However, few inhibitors of human cytomegalovirus (HCMV) have been reported so far (1,5,6,17). Since HCMY does not induce viral thymidine kinase, antiviral nucleoside analogs, which are dependent on conversion to their 5'-triphosphate forms by viral thymidine kinase, cannot inhibit HCMV replication. As a part of our design program of antiviral nucleosides, we examined the antiherpetic activities of 1-p3-D-arabinofuranosyl-5-halogenouracils (5-halo-ara-Us) and other related compounds by using HSV-1, HSV-2, and HCMV. The analogs used here are recognized as typical model compounds of

show abstract

Section: Resultsmentioning

confidence: 99%

Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil

Saneyoshi¹,

Nakayama²,

Nishiyama³

et al. 1985

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The antiviral agents were tested for toxicity to human bone marrow stem cells by the soft agar assay for CFUculture (CFU-c) as previously described (32). Briefly, marrow cells from normal donors at 2 x 105 cells per ml in supplemented McCoy 5A medium with 15% fetal calf serum and 0.3% agar were added in quadruplicate 1.0-ml portions to 35-mm petri dishes containing human placenta-derived colony-stimulating factor and various concentrations of the antiviral agents to be tested.…”

Section: Materuils and Methodsmentioning

confidence: 99%

“…Vidarabine, acyclovir (ACV), and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) are nucleoside analogs which are active against HSV and varicella-zoster virus (2,9,10,25,31). Trifluorothymidine (TFT) and (S)-9-(2,3-dihydroxypropyl)adenine (DHPA) are also nucleoside analogs with activity against HSV and CMV (9,13,30,32). Hematopoietic toxicity has been the main dose-limiting factor in the clinical use of antiviral agents.…”

mentioning

confidence: 99%

“…Mouse embryo fibroblasts and human foreskin fibroblasts were prepared and used as previously described (32). One-step replication assays for the AD169 strain of human CMV in human foreskin fibroblasts were conducted over % h, and titers were determined as previously described (32). One-step replication assays for a clinical isolate of HSV type 1 in mouse embryo fibroblasts were conducted over 24 h, and titers were determined in Vero cells as previously described (6).…”

mentioning

confidence: 99%

“…Cells and antiviral assays. Mouse embryo fibroblasts and human foreskin fibroblasts were prepared and used as previously described (32). One-step replication assays for the AD169 strain of human CMV in human foreskin fibroblasts were conducted over % h, and titers were determined as previously described (32).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Effect of several antiviral agents on human lymphocyte functions and marrow progenitor cell proliferation

Wingard¹,

Hess²,

Stuart³

et al. 1983

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Toxicity to hematopoiesis and lymphocytic function are major considerations in the clinical applicability of antiviral agents. We have examined the toxicities of five antiviral agents showing activity against herpesviruses: vidarabine, acyclovir, (E)-5-(2-bromovinyl)-2'-deoxyuridine, trifluorothymidine, and (S)-9-(2,3-dihydroxypropyl)adenine. The drugs were tested in vitro for inhibition of herpes simplex virus type 1 and human cytomegalovirus replication, effects on marrow progenitor cell growth, effects on lymphocyte responses to mitogen and alloantigen stimulation, and effects on several lymphocyte cytotoxic responses. In general, lymphocyte proliferative responses were inhibited by the various drugs at lower concentrations than were cytotoxic activities. Acyclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine were the least toxic drugs tested, with antiviral indices exceeding 10,000. Vidarabine and trifluorothymidine were more toxic, with antiviral indices generally between 10 and 100. (S)-9-(2,3-dihydroxypropyl)-adenine was the most toxic, with several antiviral indices between 1 and 10.

show abstract

Antiviral Agents

Hosmane

2003

Kirk-Othmer Encyclopedia of Chemical Technology

View full text Add to dashboard Cite

Since the discovery of the first virus >100 years ago, thousands of different viruses have been identified and characterized, and a number of plant, animal, and human ailments have been traced to viral origin. The rapid advances made in tools and techniques of molecular biology in the last 40 years, coupled with cooperative efforts in genetics and biochemical fronts, have afforded intricate details of the structure, function, replication, and genomic makeup of a host of viruses. As there are too many viruses to give even short accounts, this article focuses on only those that have some relevance to human diseases. But, since the list of all human viruses would still be too long to give detailed descriptions for each, the focus is further narrowed down to four major viruses that are currently perceived to threaten global health. These four viruses include HIV (human immunodeficiency virus, which causes AIDS), HBV and HCV (hepatitis B and C viruses that cause liver damage), and the more recent WNV (West Nile virus that causes brain inflammation). Nevertheless, an attempt has been made to classify all the known major viruses based on their shape, size, symmetry, hosts, and chemical composition that includes nucleic acid, protein, and presence or absence of lipid envelope. As they are a form of life that cannot replicate outside a host cell, viruses have evolved to develop complex and diverse interactions with higher organisms. Therefore, it was long believed that the development of antiviral agents that would specifically disrupt the viral replication process without affecting the normal metabolic events of the host would be difficult. Thanks to excellent advances in virology, several targets that are unique to the viruses have now been identified and successfully explored. This article briefly describes the general processes of viral infection to point out potential targets for selective antiviral agents. These targets are then classified into two major virus‐specific processes, including ( a ) early events of viral adsorption, penetration and uncoating, and ( b ) later synthetic events that concern intracellular replication of the virus. While there are only limited choices of candidates dealing with the early events, a much larger pool of candidates exists for targeting the later events in a virus life cycle, and they are known to be virus‐specific. The viruses synthesize and utilize specific enzymes and proteins, and more importantly, the replication of viral genomes is also virus‐specific. Nucleoside analogues which target these later events of viral life cycles have played major roles as antiviral agents against almost all the major viruses, and therefore, a special emphasis has been placed on this class of compounds in this review article. Prophylactic measures such as vaccine immunization have also been discussed under each of the four major viruses mentioned.

show abstract

Activity of trifluorothymidine against cytomegalovirus

Cited by 30 publications

References 26 publications

Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil

Mechanism of selective inhibition of human cytomegalovirus replication by 1-beta-D-arabinofuranosyl-5-fluorouracil

Effect of several antiviral agents on human lymphocyte functions and marrow progenitor cell proliferation

Antiviral Agents

Contact Info

Product

Resources

About