Effects of Certain Nucleoside Analogues on Human Cytomegalovirus Replication in vitro

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

Section: Resultsmentioning

confidence: 99%

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Koshida

Cox

Harmenberg

et al. 1989

“…Antiviral drugs such as vidarabine and acyclovir, which are beneficial in the clinical treatment of certain herpes simplex and varicella-zoster virus infections (7, 10, 12, 16,23,34,37), have shown little efficacy in the treatment of HCMV infections (30,33,42). In contrast, phosphonoformate and other PP, analogs (14,43) and certain 2'-fluoro-5-substituted arabinosylpyrimidines (8,29) have some efficacy against HCMV in vitro. One promising compound, ganciclovir (also known as DHPG, BW759U, 2'-NDG, and BIOLF-62) (17,28,31), is a potent and selective inhibitor in vitro and is currently undergoing clinical trials for the treatment of HCMV infections in bone marrow transplant and acquired immunodeficiency syndrome patients (9).…”

mentioning

confidence: 99%

Pyrrolo[2,3-d]pyrimidine nucleosides as inhibitors of human cytomegalovirus

Turk¹,

Shipman²,

Nassiri³

et al. 1987

128

188

Seven arabinosyl, 2'-deoxyribosyl, and ribosyl pyrrolo[2,3-dlpyrimidines were evaluated in vitro for activity against human cytomegalovirus and for cytotoxicity in primary and established cell lines of human origin. The parent ribosyl analogs exhibited little antiviral selectivity owing to high cytotoxicity. In contrast, aratubercidin, ara-toyocamycin, ara-sangivamycin, and deoxysangivamycin exhibited selectivity between antiviral effect (measured by plaque or titer reduction or both) and cytotoxicity (measured microscopically and by incorporation of radioactive precursors into DNA, RNA, and protein). The selectivity (in vitro therapeutic indexes) for these four compounds ranged from 2 to 40. The two sangivamycin analogs were the most potent and selective. Ara-sangivamycin, for example, inhibited virus replication 105-fold at a concentration (10 ,uM) which produced only partial inhibition of cell growth and labeled precursor incorporation. The four arabinosyl and deoxyribosyl nucleosides appeared to act by inhibition of viral DNA synthesis as quantitated by DNA-DNA dot blot hybridization. These four analogs also were tested for activity against two strains of type 1 herpes simplex virus by a plaque reduction assay. Unexpectedly, all compounds inhibited herpes simplex virus to a lesser extent than human cytomegalovirus.

“…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.…”

mentioning

confidence: 99%

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

Saneyoshi¹,

Nakayama²,

Nishiyama³

et al. 1985

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