5'-Fluoro-5'-deoxyaristeromycin

5'-Fluoro-5'-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentylidenedioxy)-4-fluoromethylcyclopentan-1-ol with N6-bis-boc protected adenine. This procedure is adaptable to preparing a number of 5'-fluoro-5'-deoxycarbocyclic nucleoside analogs with diversity in the heterocyclic base. Antiviral analysis found promising activity for 2 toward measles but no other viruses. No cytotoxicity was observed for 2.     

5-substituted arabinofuranosyluracil nucleosides: synthesis and antiviral properties

A number of 5-alkyl (ethyl, propyl, isopropyl, butyl) analogues of araU, their alpha-anomers and N3-isomers have been synthesized by a number of different procedures, based on the catalytic condensation of the appropriate 5-alkyl-2,4-bis-(trimethylsilyloxy)-pyrimidine with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride. The resulting protected nucleosides were deblocked by a new procedure based on the use of BF3 X Et2O in C2H5SH. The chloromercuri derivative of araU, on reaction with allyl chloride in the presence of Li2PdCl4, gave the 5-allyl derivative, which was catalytically reduced to the corresponding 5-propyl analogue. The antiviral activities of these compounds have been evaluated. 5-Allyl-araU showed moderate specific activity (MIC 20 micrograms/ml) against herpes simplex type 1 virus in PRK cell cultures. Structure-activity relationships are discussed for the 5-alkyl deoxy- and arabino- uracil nucleoside series.     

Radical-regulating and antiviral properties of ascorbic acid and its derivatives

The ability of ascorbic acid and a number of its derivatives to suppress replication of Herpes simplex virus type I was investigated in human rhabdomyosarcoma cell line. In parallel, interaction of the test compounds with carbon- and oxygen-centered radicals formed on radiolysis of hydroxyl-containing organic compounds was studied using the steady state radiolysis method. It has been shown that 2-O-glycoside of ascorbic acid, displaying marked antiviral properties against Herpes simplex virus type I, is also capable of inhibiting fragmentation and recombination reactions of α-hydroxyl-containing carbon-centered radicals while not affecting processes involving oxygen-centered radicals.     

Synthesis of nucleoside 5'-fluoroalkylphosphonate--compounds with potential antiviral properties]

Several 5'-fluoroalkylphosphonates of 3'-azido-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine were synthesized as potential antiviral compounds. Fluoromethyl, difluoromethyl, fluorochloromethyl and vinyl phosphonates were used as phosphonylating components, with dicyclohexylcarbodiimide or triisopropylbenzenesulphonyl chloride as condensing reagents.     

5 '-Amino-4-imidazolecarboxamide riboside induces apoptosis in human neuroblastoma cells via the mitochondrial pathway

5'-Amino-4-imidazolecarboxamide (AICA) riboside induces apoptosis in neuronal cell models. In order to exert its effect, AICA riboside must enter the cell and be phosphorylated to the ribotide. In the present work, we have further studied the mechanism of apoptosis induced by AICA riboside. The results demonstrate that AICA riboside activates AMP-dependent protein kinase (AMPK), induces release of cytochrome c from mitochondria and activation of caspase 9. The role of AMPK in determining cell fate is controversial. In fact, AICA riboside has been reported to be neuroprotective or to induce apoptosis depending on its concentration, cell type or apoptotic stimuli used. In order to clarify whether the activation of AMPK is related to apoptosis in our model, we have used another AMPK stimulator, metformin, and we have analysed its effects on cell viability, nuclear morphology and AMPK activity. Five mM metformin increased AMPK activity, inhibited viability, and increased the number of apoptotic nuclei. AICA riboside, which can be generated from the ribotide (an intermediate of the purine de novo synthesis) by the action of the ubiquitous cytosolic 5'-nucleotidase (cN-II), may accumulate in those individuals in which an inborn error of purine metabolism causes both a building up of intermediates and/or an increase of the rate of de novo synthesis, and/or an overexpression of cN-II. Therefore, our results suggest that the toxic effect of AICA riboside on some types of neurons may participate in the neurological manifestations of syndromes related to purine dismetabolisms.     

Double-stranded RNA from phage F6: its interferon-inducing and antiviral properties]

Double stranded RNA was isolated from bacteriophage phi 6 parasitizing on phytobacteria. Its interferon-inducing and antiviral activities were shown in vitro and in vivo. In the culture of L-929 cells, interferon resistant to heat and acids was synthesized. The interferon could be practically completely neutralized by specific anti-interferon serum. The phage phi 6 preparation dsRNA in the lyophilized form was studied. The preparation retained its biological activity. It was shown that a preparation containing 30 per cent of dsRNA was less toxic than a preparation containing 100 per cent of dsRNA, the difference in the interferon-inducing activity being insignificant.     

5-Formyl-2'-deoxyuridine: cytostatic and antiviral properties and possible modes of action.

5-Formyl-2'-deoxyuridine (fdUrd) was prepared by a new method starting from thymidine and investigated for its influence both on proliferation of cultured mammalian cells and virus replication in vitro. The compound was found to have strong cytostatic and antiviral properties: 50% inhibition of proliferation of BHK 21/C13 cells or Ehrlich ascites tumour cells (EAT) was obtained at 4 - 10(-6) and 6 - 10(-6) M, respectively, while the treatment of pseudorabies virus with the same concentration resulted in about 1.5 log reduction of virus yield. A concentration of 1 - 10(-4) M inhibited cell proliferation by 80 to 100% while the virus yield was reduced by more than 3 orders of magnitude. All inhibitions can be prevented by thymidine.--DNA synthesis of EAT cells in vitro, as estimated by incorporation of [32P]-phosphate or low concentrations of [3H]-thymidine, was inhibited. Further biochemical experiments have provided indirect evidence that the compound is phosphorylated by thymidine and thymidylate phosphorylating enzymes. An inhibition of cell free DNA synthesis was found to be depending on a given period of preincubation with the compound (supposed to be needed for the formation of fdUrd 5'-triphosphate). This suggests that the 5'-triphosphate of fdUrd is an inhibitor of DNA polymerases and--by analogy with experiments with 5-formyluridine-5'-triphosphate and RNA polymerases [14]--may be used as an affinity label for this group of enzymes. It is concluded that the described cytostatic and antiviral effects of fdUrd are due to an intracellular "lethal" synthesis of the relevant phosphates which inhibit thymidylate synthetase (as had been found earlier to occur with the chemically prepared nucleotide in cell free extracts [1, 2]) and DNA synthesizing enzymes.     

Dimerization properties of Rabaptin-5 and its isoforms

Rabaptin-5 plays an important role in intracellular membrane traffic acting as an effector molecule of small GTPases Rab5 and Rab4. It was previously demonstrated that Rabaptin-5 exists as a part of a large protein complex in vivo and is able to form dimers in vitro. Data of X-ray structural analysis suggest that dimerization of Rabaptin-5 is an important feature required for its interaction with Rab5 GTPase. Recently several isoforms of Rabaptin-5 characterized by various deletions in the polypeptide chains have been identified. These isoforms might exhibit functional properties that differ from those of Rabaptin-5. In this study, we have investigated dimerization properties of delta and gamma isoforms of Rabaptin-5. In addition, we have provided the first direct evidence for Rabaptin-5 dimerization in cells.     

Synthesis and antiviral properties of aza-analogues of acyclovir

Aza-analogues of Acyclovir were obtained from N-(2-pivaloyloxyethyl)-N-(pivaloyloxymethyl)-p-toluenesulfonamide via a one-pot base silylation/nucleoside coupling procedure. The antiviral activities of all aza-nucleosides in vitro against a variety of viruses were evaluated. None of these compounds displayed any specific antiviral effects.     

4'-C-modified nucleosides: synthesis and antiviral properties

The synthetic methods for 4'-C-modified nucleosides as well as structure activity relationship of obtained compounds towards hepatitis C virus are reviewed.     

Synthetic proteins with antiviral properties of alpha-interferons

Consensus sequence 30-36 LKDRHDF of human alpha-interferons is inserted into the C- and N-terminal sequences of the artificial protein albeferon using genetic engineering methods in order to obtain artificial proteins with antiviral activity. Albeferon, obtained by Dolgikh et al. (Protein Eng., 1996, vol. 9, pp. 195-201), already contains the IFN-alpha 2 130-137 fragment and possesses antiproliferative activity comparable with that of IFN-alpha 2. According to CD spectroscopy, both proteins have regular secondary structures similar to that of the precursor protein. They exhibit antiviral activities, and the activity of one of them is comparable with that of IFN-alpha 2. At the same time, their cytotoxic properties are displayed only at relatively high concentrations, which substantially exceed the minimal antiviral concentrations.     

RNA干扰及其抗病毒应用的可行性探讨

RNA干扰是存在于动植物细胞中的,由双链RNA介导的,序列特异性的mRNA降解过程。在哺乳动物细胞里,RNAi可以由21￣25个核苷酸长度的双链小干扰RNA(siRNA)触发。目前,以RNAi为策略来抑制病毒复制的方法已获得了巨大成功。但RNAi具有高度序列特异性,而多种病毒,如HIV-1、HBV A等却具有迅速变异的倾向。本文就病毒进化出的多种逃避RNA干扰的机制以及如何降低病毒对RNAi的耐受力等问题进行了多方面的探讨。     

Isolation of marine bacteria with antiviral properties

We report in this study the isolation of marine bacteria with antiviral properties that have been tentatively classified as Moraxella. These bacteria retained their virucidal capacity after prolonged subcultivation in the laboratory. The virus-inactivating agent could not be separated from the viable marine bacteria, indicating that the active agent(s) either remains associated to the microorganisms or has a very short lifetime, or both. The antiviral capacity of the isolated microorganisms was highly specific for poliovirus. No virucidal effect was observed against other strains of enteroviruses, such as Coxsackie and ECHO virus, rotavirus SA11, or bacteriophages proposed as indicators of the virological quality of water, such as coliphage f2 and bacteriophage B40-8, which infects Bacteroides fragilis.     

4′-C-nucleoside derivatives: Synthesis and antiviral properties

Synthesis of 4′-C-modified nucleosides and their derivatives, as well as the structure-activity relationship toward hepatitis C virus were discussed.     

l-like 3-deazaneplanocin analogues: Synthesis and antiviral properties

The potent antiviral properties of 3-deazaneplanocin, 3-deaza-isoneplanocins (1) and recently discovered l-like carbocyclic nucleosides (2, 3 and 4) prompted us to pursue rationally conceived l-like 3-deazaneplanocin analogues. The synthesis of those analogues including l-like 3-deazaneplanocin (5), l-like 3-bromo-3-deazaneplanocin (6), and l-like 5′-fluoro-5′-deoxy-3-deazaneplanocin (7), was accomplished from a common intermediate, (−)-cyclopentenone (8). Antiviral analysis found 5 and 6 to display favorable activity against the Ebola virus, as expected for 3-deazaadenine carbocyclic nucleosides. Compound 5 also showed activity against arenaviruses, including Pinchinde and Tacaribe.     

Immunostimulatory properties and antiviral activity of modified HBV-specific siRNAs

Sequence-specific gene silencing by small interfering RNA (siRNA) is an intense area of focus in the development of novel therapeutic agents. Currently, there are two major hurdles to achieving clinically effective siRNA-based therapeutics: establishment of an efficient delivery system that transfers the siRNA to the correct tissue(s); and the reduction of unintended immunotoxicity associated with unmodified siRNA. We have developed a novel liver-specific delivery system of apolipoprotein A-I-decorated cationic lipids (DTC-Apo). Here, we show that intravenous injection of an unmodified hepatitis B virus (HBV)-specific siRNA encapsulated in DTC-Apo activates the innate immune response in mice. However, 2′-O-methyl (2′-OMe) modification of siRNA sense-strand uridine or uridine/adenosine residues efficiently abrogated the immunostimulatory properties of the siRNA and also silenced viral replication. In contrast, pyrimidine modification by 2′-OMe or 2′-fluoro (2’-F) substitution failed to circumvent liposome-induced immune recognition. Our findings provide useful information for the design of chemically-modified siRNAs for in vivo applications.     

白藜芦醇抗菌抗病毒作用的研究进展

白藜芦醇是一种天然活性物质,被认为是植物体在恶劣环境下受到病原菌感染,植物自身分泌的一种抗毒素,对植物本身起保护作用。随着对白藜芦醇研究的深入,发现白藜芦醇具有抗肿瘤、抗心血管疾病、治疗突变、抗氧化、抗菌抗炎、保肝、诱导细胞凋亡等生物药理活性。近年来,国内外很多学者对白藜芦醇的部分生物学功能进行了深层研究,但关于白藜芦醇抗菌、抗病毒的研究报道较少,本研究对近年来发现的白藜芦醇可抵抗的病原生物,按细菌、真菌、病毒进行分类列举,并对其部分已知抗菌抗病毒机制进行归纳。