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PubMedDate not supplied

Novel cyanine dye-labeled dideoxynucleoside triphosphates for DNA sequencing.

Single color cyanine dye-labeled (Cy 5.0 and Cy 5.5) dideoxynucleoside-5'-triphosphates, or 'terminators', containing different spacer lengths were synthesized and evaluated for efficacy in DNA sequencing methods using a modified thermally stable DNA polymerase. The single color cyanine dye terminators were formulated into two separate sets of sequencing mixes, one for Cy 5.0 and the other for Cy 5.5, and evaluated on different automated sequencing platforms. Each set of mixes included two pyrimidine terminators with 17-atom linkers and two purine terminators with 10-atom linkers between the dye and the nucleotide. The two sets of cyanine dye-labeled terminators chosen for this cycle sequencing study produced improved band patterns with band uniformity similar to that obtained with dye-primer sequencing methods.

Base Sequence↗
PubMed1990

5'-O-phosphonomethyl-2',3'-dideoxynucleosides: synthesis and anti-HIV activity.

5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl [(p-toylsulfonyl)oxy]methanephosphonate (1) in the presence of sodium hydride. The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis. Protection of the uracil or thymine residue with a N3-benzoyl group failed to prevent base modification. However, O4-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylated derivative 12, which was converted to both the 2',3'-didoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29. The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine, (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 microM.

Antiviral Agents↗
PubMed2005

Electrooxidative glycosylation through C-S bond cleavage of 1-arylthio-2,3-dideoxyglycosides. Synthesis of 2',3'-dideoxynucleosides.

[reaction: see text] The electrooxidative glycosylation of newly designed 1-arylthio-substituted 2,3-dideoxyglycosides is described. The halide salt-mediated electrooxidation utilizing either of the alpha- or beta-thiodideoxyglycosides proceeded smoothly at -78 degrees C to give dideoxynucleosides in a beta-selective manner, presumably through a 1-halo-substituted glycosyl donor.

Anti-HIV Agents↗
PubMed1996

Localization of purine metabolizing enzymes in bovine brain microvessel endothelial cells: an enzymatic blood-brain barrier for dideoxynucleosides?

PURPOSE: The specific activities of the purine and pyrimidine metabolizing enzymes, purine nucleoside phosphorylase (PNP), adenosine deaminase (ADA) and cytidine deaminase (CDA) were determined in bovine brain microvessel endothelial cells (BBMECs), whole cerebral tissue and erythrocytes. In addition, the substrate specificities (Km and Vmax) of purified calf spleen PNP for inosine and 2',3'-dideoxyinosine (ddI) and of purified calf intestinal ADA for 2',3'-dideoxyadenosine (ddA), 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), and 2'-beta-fluoro-2', 3'-dideoxyadenosine (F-ddA) have been explored. METHODS: BBMECs were isolated from bovine cerebral cortex by a two step enzymatic dispersion treatment followed by centrifugation over 50% Percoll density gradients. Activities of alkaline phosphatase, gamma-glutamyl transpeptidase, ADA, PNP and CDA were determined in various tissue homogenates (cerebral cortex, BBMECs and erythrocytes). Enzyme kinetic studies were also conducted using commercially available enzymes and several nucleoside analogs of interest. RESULTS: The activities of ADA and PNP were 42-fold and 247-fold higher in the cerebral microvessels than in the cerebral cortex, respectively, while there was no detectable CDA activity in the microvessel fraction and very little overall activity in the cortex. CONCLUSIONS: ADA and PNP may serve as an enzymatic blood-brain barrier for some of the anti-HIV dideoxynucleosides. Simulations of brain availability for ddI, ddA, 6-Cl-ddP, and F-ddA demonstrated that the quantitative significance of enzyme localization may vary dramatically, however, depending on the membrane permeability of the drug and its bioconversion rate constant within the endothelial cell.

Adenosine Deaminase↗
PubMedDate not supplied

Synthesis and antiviral studies of unsaturated analogues of isomeric dideoxynucleosides.

Novel isomeric dideoxynucleosides with unsaturation in the carbohydrate moiety have been synthesized. For example, isod4A was synthesized through a rearrangement reaction involving a cyclonucleoside. Support for the structures of both purine and pyrimidine d4 compounds came from UV, NMR, HRMS and single crystal X-ray data. Interestingly, the single crystal X-ray data for isod4C shows that the base is almost orthogonal to the carbon-carbon double bond of the sugar moiety. Consistent with this is the observation that the UV data of this compound does not show a bathochromic shift compared to the saturated compound implying that the pi-bond is not in conjugation with the pyrimidine base.

Anti-HIV Agents↗
PubMedDate not supplied

Synthesis of isoxazolidino analogues of 2',3'-dideoxynucleosides.

The complete set of the 4'-aza analogues of 2',3'-dideoxynucleosides was synthesized by cycloaddition of N-tetrahydropiranyl or N-trityl methylene nitrones on suitably protected vinyl nucleobases. The convertible nucleoside approach was used in the preparation of cytosine and 5-methyl cytosine analogues.

Dideoxynucleosides↗
PubMedDate not supplied

3'-(N-hydroxyimino)-2',3-dideoxynucleosides and their derivatives: synthesis, broad spectrum antiviral properties and synthetical application for the preparation of other nucleoside analogues.

A series of 3'-(N-hydroxyimino)-2',3'-dideoxynucleosides bearing different nucleic bases has been prepared. In vitro antiviral activity studies showed that among these compounds the thymine derivative possesses significant activity against HIV, HSV, EBV and HBV. Conveniently 5'-protected 3'-(N-hydroxyimino)-2',3'-dideoxythymidine was further used as a synthon for the preparation of other nucleoside analogues.

Antiviral Agents↗
PubMedDate not supplied

Structural determinants of HIV-1 reverse transcriptase stereoselectivity towards (beta)-L-deoxy- and dideoxy-pyrimidine nucleoside triphosphates: molecular basis for the combination of L-dideoxynucleoside analogs with non-nucleoside inhibitors in anti HIV chemotherapy.

We have compared the HIV-1 RT mutants containing the single substitutions L100I, K103N, V106A, V179D, Y181I and Y188L, known to confer NNI-resistance in treated patients, to HIV-1 RT wt for their sensitivity towards inhibition by D- and L-deoxy- and dideoxy-nucleoside tiphosphates. The results showed a differential effect of the substitutions on the affinity for both D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphates and provide a rationale for the utilization of L-dideoxynucleoside analogs with NNI in combination chemotherapy.

Anti-HIV Agents↗
PubMed2001

Photochemical synthesis of novel dideoxynucleosides.

A series of 2',3'-dideoxynucleosides based on the apiose family was prepared from photochemical ring-expansion of a common cyclobutanone precursor. The starting ketone, (+/-) 3-[2'-(benzoyloxy)ethyl]-2,2-dimethylcyclobutanone (12) was prepared from commercially available (+/-)alpha-pinene. Since the optically pure antipodes of alpha-pinene are also commercially available, these nucleosides can be prepared optically pure using the identical procedure.

Anti-HIV Agents↗
PubMed1998

Emergence of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 variants, viral sequence variation, and disease progression in patients receiving antiretroviral chemotherapy.

A set of five reverse transcriptase mutations, which include Q151M, is known to confer multi-dideoxynucleoside resistance (MDR) in human immunodeficiency virus type 1 (HIV-1). MDR mutations were found in 6 (17%) HIV-1 isolates from 36 patients, most of whom were receiving long-term combination therapy. Q151M was among the first of the substitutions to appear. Additional substitutions were observed, although none were common among all 6 patients. Certain zidovudine-related mutations were not observed together with the MDR mutations, indicating possible enzymatic constraint. During chemotherapy, the HIV-1 RNA levels in the 6 patients initially decreased and then rose. Initially, CD4 cell counts also responded favorably but were near or below baseline beyond 40 months of therapy. Such loss of clinical benefits appeared to coincide with the appearance of the MDR mutations. A common background genotype was not observed among HIV-1 isolates with or without MDR.

Adult↗
PubMed1995

Comparison of metabolism and in vitro antiviral activity of stavudine versus other 2',3'-dideoxynucleoside analogues.

2',3'-dideoxynucleosides are the principal drugs used to treat AIDS and are the only drugs thus far with demonstrated clinical benefits in patients with human immunodeficiency virus (HIV) infection. Although nucleoside analogues are structurally similar and have common mechanisms of action, each drug has unique molecular, cellular, and clinical features. For example, 3'-azido-3'-deoxythymidine (zidovudine) and 3'-deoxy-2',3'-didehydrothymidine (stavudine) have similar in vitro anti-HIV activity but differ in their tendency to produce bone marrow suppression. Stavudine has been shown to be less myelosuppressive than zidovudine. With the exception of zidovudine, most of the clinically evaluated nucleoside analogues, including 2',3'-dideoxyinosine (didanosine), 2',3'-dideoxycytidine (zalcitabine), and stavudine, produce dose-dependent peripheral neuropathy. However, recent studies suggest that neuropathy induced by stavudine may be mediated by mechanisms different from those of didanosine and zalcitabine.

Animals↗
PubMed1998

Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries.

OBJECTIVE: To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterize MddNR strains genotypically and phenotypically. DESIGN AND METHODS: Blood samples from patients after > or = 6 months of treatment with multiple ddN were screened for the MddNR mutation Q151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients. RESULTS: The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations. CONCLUSIONS: MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.

Amino Acid Sequence↗
PubMed2003

Pathways for the emergence of multi-dideoxynucleoside-resistant HIV-1 variants.

OBJECTIVE: To investigate the mechanism by which the Q151M mutation in reverse transcriptase (RT) that confers multi-dideoxynucleoside resistance on HIV-1 and that requires a two base change (CAG-->ATG) develops, and to understand the reason for the relatively lengthy period of time required for its emergence under therapy with multiple nucleoside RT inhibitors (NRTI). DESIGN AND METHODS: Propagation assays and competitive HIV-1 replication assays were used to evaluate the fitness of various infectious clones, including two putative intermediates (HIV-1(Q151K(AAG)) and HIV-(1Q151L(CTG))) for HIV-1(Q151M(ATG)), in terms of sensitivity to zidovudine and didanosine. Steady-state kinetic constants of recombinant RT were also determined. RESULTS: HIV-1(Q151L) replicated relatively poorly while HIV-1(Q151K) failed to replicate. When HIV-1(Q151L) was propagated further, it took three pathways in continuing to replicate: (i) HIV-1(Q151L) changed to HIV-1(Q151M) in eight of 16 experiments; (ii) HIV-1(Q151L) reverted to wild-type HIV-1 (HIV-1(WT)) in four of 16 experiments; and (iii) HIV-1(Q151L) acquired an additional mutation M230I in four of 16 experiments improving HIV-1 fitness. The relative order of replicative fitness without drugs was: HIV-1(Q151M) > HIV-1(WT) > HIV-1(Q151L/M230I) > HIV-1(M230I) >> HIV-1(Q151L) >>> HIV-1(Q151K), HIV-1(Q151K/M230I). HIV-1(Q151M) was less susceptible to drugs, while HIV-1(Q151L/M230I) was as sensitive as HIV-1(WT). Enzymatic assays corroborated that HIV-1(Q151L) is more replication-competent than HIV-1(WT) and HIV-1(Q151K) in the presence of drugs. CONCLUSION: HIV-1(Q151M) probably develops through a poorly replicating HIV-1(Q151L); however, it is also possible that it occurs through two concurrent base changes. The present data should explain the mechanism by which HIV-1(Q151M) emerges after long-term chemotherapy with NRTI.

Anti-HIV Agents↗
PubMed1998

Marked inhibitory activity of masked aryloxy aminoacyl phosphoramidate derivatives of dideoxynucleoside analogues against visna virus infection.

Lipophilic masked aryloxyaminoacylphosphoramidate derivatives of 2',3'-dideoxynucleoside (ddN) analogues with potent anti-HIV activity (i.e., stavudine [d4T], azidothymidine [AZT], dideoxycytidine [ddC], 3'thio-2',3'-dideoxy cytidine [3TC], dideoxyadenosine [ddA], and 2',3'-didehydro-2',3'-dideoxyadenosine [d4A]) activity were evaluated for their activity against visna virus (VV) in sheep choroid plexus (SCP) cells. The activity of several prodrug derivatives against VV proved markedly superior to that of the corresponding free ddN analogues. In particular, the d4A and ddA prodrug derivatives were exquisitely inhibitory in this model system (50% effective concentration [EC50], < or = 0.003 microM), and their anti-VV potency exceeded by at least 200-fold the antiviral potency of the corresponding free nucleosides. Marked differences were noted in the anti-VV potencies of several of the test compounds depending on the nature of the amino acid linked to the 5'-phosphate moiety, the nature of the nucleoside, or both. In view of the stability of the prodrugs in lamb serum, the VV infection model in lambs may be considered highly useful for investigating the in vivo antiretroviral efficacy of these type of drugs, particularly the d4T, ddA, and d4A prodrug derivatives.

Animals↗
PubMed2000

Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a multicenter cohort of HIV-1-infected Italian patients with virologic failure.

We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat.

OBJECTIVES: Nucleoside reverse transcriptase inhibitors (NRTIs), particularly dideoxynucleoside analogs (ddNs), used in the treatment of HIV, inhibit mitochondrial DNA polymerase gamma in vitro. Mitochondrial DNA (mtDNA) depletion is proposed as the underlying mechanism of many of the in vivo side effects of these agents. A reliable and valid laboratory test to detect this is not yet available. The objective of this study was to correlate tissue mtDNA quantification in HIV-infected patients with exposure to nucleoside analogs. METHODS: 60 HIV-infected adults underwent detailed clinical assessment and blood and tissue sampling. Clinical and antiretroviral treatment details were correlated with results of plasma lactate assays, and real-time polymerase chain reaction quantification of mtDNA in peripheral blood mononuclear cells (PBMCs) and subcutaneous fat from the lower limb. RESULTS: Forty-nine (82%) subjects were on combination antiretroviral therapy. Of these, 33 (55%) were currently receiving one or more ddNs (stavudine, didanosine, or zalcitabine). mtDNA in subcutaneous fat was lower in subjects currently on ddNs than in those not taking ddNs (mean [log10] 2.47 vs. 2.74, p =.002). Plasma lactate was somewhat higher in subjects currently taking ddNs than those on no antiretroviral treatment (median 1.5 vs. 1.0, p =.03), but was not significantly different in either of these groups compared with subjects on other NRTIs. mtDNA in PBMCs did not vary with treatment status. CONCLUSIONS: mtDNA in subcutaneous fat was significantly reduced in patients currently taking ddNs. mtDNA in PBMCs was independent of patient exposure to NRTIs.

Adipose Tissue↗
PubMed1987

Inhibitory effect of 2',3'-didehydro-2',3'-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus.

It is generally accepted that human immunodeficiency virus (HIV) is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In this report, we demonstrate the antiviral effect of nucleoside analogs 2',3'-didehydro-2',3'-dideoxythymidine (DHT) and 2',3'-didehydro-2',3'-dideoxycytidine (DHC) by using human T-cell lymphotropic virus type I-carrying MT-4 cells, which are extremely susceptible to HIV infection. These agents efficiently inhibited the cytopathic effects and expression of HIV-specific antigens in MT-4 cells after infection of the virus. Both DHT and DHC also strongly blocked viral replication as determined by our quantitative bioassay system using a plaque-forming assay. These antiviral effects were obtained at concentrations at which the drugs produced little or no toxicity and were comparable to those with 3'-azido-3'-deoxythymidine and 2',3'-dideoxynucleosides. These findings warrant further investigation of the use of DHT and DHC for the treatment of the acquired immunodeficiency syndrome and related diseases.

Antigens, Viral↗
PubMed1990

Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides.

A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (beta-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddI) induced cell filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at less than 100 ng/ml. 2',3'-Dideoxythymidine (ddT) and 2',3'-dideoxy-2',3'-didehydrothymidine (D4T) induced sulA at 100 to 1,000 micrograms/ml, while 2',3'-dideoxycytidine (ddC) weakly induced prophage lambda. Activity relationships thus were AZT greater than ddA greater than or equal to ddI greater than or equal to ddG greater than ddT = D4T greater than ddC. ddA and ddI had equivalent activities in agar diffusion assays, but different activity profiles were observed in liquid microsuspension assays. The differences may be related to drug metabolism. AZT and ddA showed marginal effects in a DNA repair (preferential toxicity) assay in which E. coli WP2 and CM871 uvrA recA lexA were used. Furthermore, none of the agents was able to preferentially inhibit Bacillus subtilis M45 recA relative to wild-type strain H17. These data suggest that AZT and the dideoxynucleosides do not cause DNA lesions that are repairable by excision repair and/or error-free postreplication repair processes. Rather, the SOS response appears to be induced by DNA chain termination leading to the inhibition of DNA replication. Bacterial assays for induction of the SOS response may be useful as simple, rapid prescreens for the discovery of new anti-HIV agents. Moreover, such assays may provide an additional parameter in the evaluation of agents with demonstrated activity against HIV and other retroviruses.

Bacillus subtilis↗