WHO reports that 90% of human population is infected by different types of herpesviruses, which develop latency or cause oral and genital herpes, conjunctivitis, eczema herpeticum, and other diseases. Herpesvirus almost always accompanies HIV-infection and complicates AIDS treatment. Herpes simplex virus type 1 is one of the most wide spread viruses from the Herpesviridae family. HSV virion, genome structure, replication mechanisms, antiherpes drug development strategies, including design of prodrugs, and mutations causing ACV-resistance in clinical HSV isolates are discussed in this review.
5-Triphosphates of -D and -L-enantiomers of 2,3-dideoxycytidine (ddC), 2,3-dideoxy-5-fluorocytidine (FddC), 1,3-dioxolane-cytidine (OddC), and 1,3-dioxolane-5-fluorocytidine (FOddC) were evaluated as inhibitors and substrates for human DNA polymerases ␣, , ␥, ␦, and ⑀. L-ddCTP was not a substrate or inhibitor for any DNA polymerase studied; L-FddCTP was not an inhibitor or substrate for replicative DNA polymerases and was a less potent inhibitor of DNA polymerases ␥ and  than its D-enantiomer by 2 orders of magnitude. In contrast, all L-dioxolane analogs were potent inhibitors and chain terminators for all cellular DNA polymerases studied. The K i values of their 5-triphosphates for DNA polymerase ␥ were found to be in the following order: Several 2Ј,3Ј-dideoxynucleoside analogs have been approved for the treatment of patients with AIDS (1, 2). Among them, ddC 1 has been shown to be one of the most potent inhibitors of HIV replication. Recently, SddC was found to have potent activity against HIV (3, 4) and hepatitis B virus (5) in cell culture. It was subsequently shown that the stereoisomer LSddC (3TC) was responsible for the antiviral effect, while cytotoxicity was associated mainly with the D-enantiomer (6 -9). L-ddC and L-FddC were also found to be active against hepatitis B virus and HIV in culture without much toxicity (10 -12). In contrast to L-SddC or L-FddC, L-OddC and L-FOddC were markedly more toxic than their D-enantiomers against human leukemic CEM cells (13). The spectrum of L-OddC toxicity against human tumor cells differed from that of cytosine arabinoside. L-OddC was also shown to have activity against solid human tumors in nude mice (14). Currently, L-OddC is being evaluated further as an anticancer agent. The reason why L-OddC but not L-ddC or L-SddC has potent antitumor activity is not clear, but it is probably associated with its interference in cellular DNA synthesis. L-SddC and L-OddC were shown to be phosphorylated by cellular kinases to the corresponding 5Ј-triphosphate metabolites inside cells. The antiviral effects of nucleoside analog are due to preferential interference with viral replication caused by incorporation into DNA by viral DNA polymerase. The interaction of 5Ј-triphosphate metabolites of L-OddC or L-FddC with cellular DNA polymerases may be one of the key factors in determining L-OddC cytotoxicity.In the present paper, the interaction of 5Ј-triphosphates of Dand L-enantiomers of 2,3-dideoxycytidine and 1,3-dioxolanecytidine as well as their 5-fluoro-derivatives with human pol ␣, pol , pol ⑀, pol ␦, and pol ␥ is reported. EXPERIMENTAL PROCEDURES Materials and Compounds-L-and D-stereoisomers of ddC and OddCand their 5-fluoro-derivatives were synthesized as described previously (11,13). The triphosphate forms of these compounds were synthesized in our laboratory (15). Unlabeled dNTP and ddNTP were purchased from Boehringer Mannheim. Poly(rA)⅐oligo(dT) 10 and poly(dA)⅐oli-go(dT) 12-18 were obtained from Pharmacia Biotech Inc.ssDNA cellulose was obtained from Sigma. DEAE c...
This short review is focused on enzymatic properties of human ATP-dependent RNA helicase DDX3 and the development of antiviral and anticancer drugs targeting cellular helicases. DDX3 belongs to the DEAD-box proteins, a large family of RNA helicases that participate in all aspects of cellular processes, such as cell cycle progression, apoptosis, innate immune response, viral replication, and tumorigenesis. DDX3 has a variety of functions in the life cycle of different viruses. DDX3 helicase is required to facilitate both the Rev-mediated export of unspliced/partially spliced human immunodeficiency virus (HIV) RNA from nucleus and Tat-dependent translation of viral genes. DDX3 silencing blocks the replication of HIV, HCV, and some other viruses. On the other hand, DDX displays antiviral effect against Dengue virus and hepatitis B virus through the stimulation of interferon beta production. The role of DDX3 in different types of cancer is rather controversial. DDX3 acts as an oncogene in one type of cancer, but demonstrates tumor suppressor properties in other types. The human DDX3 helicase is now considered as a new attractive target for the development of novel pharmaceutical drugs. The most interesting inhibitors of DDX3 helicase and the mechanisms of their actions as antiviral or anticancer drugs are discussed in this short review.
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