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PubMed1994

Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives.

Unlike herpes viruses, human immunodeficiency virus and other retroviruses do not encode specific enzymes required for the metabolism of the purine or pyrimidine nucleotides to their corresponding 5'-triphosphates. Therefore, 2',3'-dideoxynucleosides and acyclic nucleoside phosphonates must be phosphorylated and metabolized by host cell kinases and other enzymes of purine and/or pyrimidine metabolism. Different animal species (or even different cell types within one animal species) may differ in the efficiency of conversion of these drugs to their antivirally active metabolite(s). Three 2',3'-dideoxynucleosides are officially licensed for clinical use [i.e., zidovudine (3'-azido-2',3'-dideoxythymidine, AZT), didanosine (2',3'-dideoxyinosine, DDI) and zalcitabine (2',3'-dideoxycytidine, DDC)]. A number of other 2',3'-dideoxynucleoside analogues [among them stavudine (2',3'-didehydro-2',3'-dideoxythymidine, D4T), 2',3'-dideoxy-3'-thiacytidine (3TC), 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) and the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA)] are currently under clinical investigation and are candidate compounds for eventual licensing as anti-AIDS drugs. The metabolic pathways, antimetabolic effects and mechanism of antiviral action of these nucleoside analogues will be discussed.

Animals↗
PubMed1994

Evaluation of the genotoxic potential of selected anti-AIDS treatment drugs at clinical doses in vivo in mice.

Six anti-AIDS drugs were assessed for in vivo genotoxicity and cytotoxicity at human clinical doses with the mouse bone marrow micronucleus assay. These included four dideoxynucleosides (azidothymidine, dideoxycytidine, dideoxyadenosine, and dideoxyinosine), an anthracycline antibiotic (doxorubicin), and a chelating agent (D-penicillamine). Cytological analysis of the mouse bone marrow cells revealed: (i) The dideoxynucleosides and D-penicillamine failed to induce significant number of micronuclei, and except for one of the five doses of dideoxyinosine, none of the dideoxynucleosides were cytotoxic at the doses tested. (ii) Doxorubicin induced micronuclei in a dose-dependent manner which was statistically significant at 4-times the clinical dose but was not cytotoxic at any of the doses tested.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Molecular basis for the enantioselectivity of HIV-1 reverse transcriptase: role of the 3'-hydroxyl group of the L-(beta)-ribose in chiral discrimination between D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphate analogs.

In order to identify the basis for the relaxed enantio-selectivity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and to evaluate possible cross-resistance patterns between L-nucleoside-, D-nucleoside- and non-nucleoside RT inhibitors, to be utilised in anti-HIV-1 combination therapy, we applied an in vitro approach based on the utilisation of six recom-binant HIV-1 RT mutants containing single amino acid substitutions known to confer Nevirapine resistance in treated patients. The mutants were compared on different RNA/DNA and DNA/DNA substrates to the wild type (wt) enzyme for their sensitivity towards inhibition by the D- and L-enantiomers of 2'-deoxy- and 2',3'-dideoxynucleoside triphosphate analogs. The results showed that the 3'-hydroxyl group of the L-(beta)-2'-deoxyribose moiety caused an unfavourable steric hindrance with critic residues in the HIV-1 RT active site and this steric barrier was increased by the Y181I mutation. Elimination of the 3'-hydroxyl group removed this hindrance and significantly improved binding to the HIV-1 RT wt and to the mutants. These results demonstrate the critical role of both the tyrosine 181 of RT and the 3'-position of the sugar ring, in chiral discrimination between D- and L-nucleoside triphosphates. Moreover, they provide an important rationale for the combination of D- and L-(beta)-dideoxynucleoside analogs with non-nucleoside RT inhibitors in anti-HIV chemotherapy, since non-nucleosideinhibitors resistance mutations did not confer cross-resistance to dideoxynucleoside analogs.

Anti-HIV Agents↗
PubMed2000

Analysis of single nucleotide polymorphisms by primer extension and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

A method for typing single nucleotide polymorphisms (SNPs) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) is described, in which a mass-tagged dideoxynucleoside triphosphate is employed in a primer extension reaction in place of an unmodified dideoxynucleoside triphosphate (ddNTP). The increased mass difference due to the presence of the mass-tag greatly facilitates the accurate identification of the added nucleotide, and is particularly useful for typing heterozygous samples. Twenty commercially available mass-tagged dideoxynucleoside triphosphates were screened for amenability to incorporation by AmpliTaq FS and ThermoSequenase DNA polymerases in single nucleotide primer extension (SNuPE) reactions. Several sample preparation and purification methods were also examined and compared. Float dialysis was found to be a simple, versatile, and effective method for purification of the extension products. High specificity and sensitivity were obtained, and all six possible biallelic SNP heterozygotes were determined accurately using a 44-mer synthetic oligonucleotide target DNA as a model system. Further validation of the method was demonstrated in the analysis of five single-base mutations in exon IV of the human tyrosinase gene. Single nucleotide variations within 182-bp PCR amplicons amplified from three plasmid and three human genomic DNA samples were genotyped at five variable positions, with results in 100% concordance with conventional sequencing. Genotypes were determined accurately at five sequence-tagged sites (STSs).

Base Sequence↗
PubMed2000

Use of cultured cerebral capillary endothelial cells in modeling the central nervous system availability of 2',3'-dideoxyinosine.

The biochemical and physiological mechanisms responsible for the limited central nervous system (CNS) uptake of dideoxynucleoside reverse transcriptase inhibitors currently used to treat HIV-1 infection in humans are poorly understood. In vitro models of the blood-brain barrier (BBB) offer an attractive alternative to in vivo or in situ animal studies for understanding the role of the blood-brain barrier in regulating brain tissue concentrations of these agents. In the present study, the kinetics of 2', 3'-dideoxyinosine (ddI) uptake and purine nucleoside phosphorylase (PNP) mediated catabolism in primary cultures of bovine brain microvessel endothelial cells (BBMECs) were determined in order to ascertain the importance of both transport and metabolism governing the CNS availability of this purine dideoxynucleoside. Initial rates of ddI uptake as a function of ddI donor concentration suggest the involvement of both passive diffusion and carrier-mediated processes. These studies confirm earlier in vivo findings that transporters may play a role in regulating the CNS concentration of ddI. Analysis of ddI uptake and metabolite accumulation in BBMECs over longer time intervals (beyond the intial rate region) provide substantial in vitro evidence for an enzymatic BBB for ddI. Simulations of the CNS availability of ddI derived from in vitro estimates of parameters for passive diffusion, carrier-mediation, and metabolism indicate that the fraction of ddI entering the BBB cells which actually reaches the brain parenchyma may be quite low (< 2%) due to metabolism by PNP localized within the BBB, consistent with the low CNS delivery of ddI observed in vivo. Transporters and metabolic enzymes within the BBB may function in coordinated fashion to reduce the CNS concentrations of both rapidly metabolized and poorly metabolized dideoxynucleosides.

Animals↗
PubMed1995

Stereoselective synthesis, chemistry and antiviral evaluation of 1-(2,3-dideoxy-3-C-hydroxymethyl-beta-D-threo-pentofuranosyl)thymine derivatives.

A series of novel 3'-C-branched 2',3'-dideoxynucleosides have been synthesized and evaluated as anti-HIV agents. Hydroboration of 2',3'-dideoxy-3'-C-methylene nucleoside proceeded regio- and stereoselectively to give 1-(2,3-dideoxy-3-C-hydroxy methyl-5-O-trityl-beta-D-threo-pentofuranosyl)thymine (5) after oxidation. 3'-C-Chloromethyl and 3'-C-iodomethyl 5'-O-protected 2',3'-dideoxynucleosides 9 and 12 were obtained from 5 by reaction with carbon tetrachloride/triphenylphosphine and methyltriphenoxyphosphonium iodide, respectively. Arbuzov reaction of 12 with triethyl phosphite afforded 3'-C-(diethyl-phosphono)methyl 5'-O-protected 2',3'-dideoxynucleoside 14. Compounds 5, 9, 12 and 14 were detritylated to give 1-(3-C-chloromethyl-2,3-dideoxy-beta-D-threo-pentofuranosyl)thymine (10), 1-(2,3-dideoxy-3-C-hydroxymethyl-beta-D-threo-pentofuranosyl)-thymine (11), 1-(2,3-dideoxy-3-C-iodomethyl-beta-D-threo-pentofuranosyl)thymine (13) and 1-(2,3-dideoxy-3-C-(O,O'-diethylphosphono)methyl-beta-D-threo- pentofuranosyl)thymine (15), respectively. These nucleoside analogues were evaluated for antiviral activity against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1) in vitro. Compound 5 demonstrated selective antiviral activity against HIV-1 but not HSV-1.

Antiviral Agents↗
PubMed1994

Conformationally locked nucleoside analogues. Synthesis of dideoxycarbocyclic nucleoside analogues structurally related to neplanocin C.

The glycon moiety of nucleosides in solution is known to exist in a rapid dynamic equilibrium between extreme northern and southern conformations as defined by the pseudorotation cycle. The concept of preparing rigid nucleoside analogues with the glycon conformation locked in one of these two extremes was tested with the synthesis of some cyclopropane-fused dideoxycarbocyclic nucleosides, similar to the well-known class of anti-HIV active dideoxynucleosides. The new compounds described here are dideoxynucleoside analogues of the fermentation product neplanocin C (6) which exhibits a typical northern geometry for its 6-oxabicyclo[3.1.0]hexane pseudosugar moiety. However, in view of the lability of the epoxide ring in this system, the equivalent cyclopropane-fused bicyclo[3.1.0]hexane system was used instead to prepare the corresponding dideoxynucleoside analogues bearing all the common bases [(+/-)-9-13]. Due to the well-documented preference of unrestricted bicyclo[3.1.0]hexane systems to exist exclusively in a boat conformation, the resulting nucleosides are structurally locked in a typical northern conformation similar to that of neplanocin C. The locked northern conformation in these nucleosides remained unchanged in solution in the 20-80 degrees C temperature range according to variable temperature 1H NMR studies. For the synthesis of these compounds, racemic trans-1-[(benzyloxy)methyl]-4-hydroxybicyclo[3.1.0]hexane [(+/-)-18] was prepared by a samarium-promoted cyclopropanation reaction with the antecedent cyclopentenol. All of the bases were incorporated under Mitsunobu conditions and converted to the desired final products following a standard methodology. Anti-HIV evaluation revealed that only the adenosine analogue (+/-)-9 possessed enough activity to warrant resolution into its optical antipodes. This was realized by chiral HPLC chromatography to give the individual enantiomers (-)-32 and (+)-33. Adenosine deaminase was used to identify isomer (+)-33 as the enantiomer with the "natural" configuration which was solely responsible for the observed biological activity and toxicity of (+/-)-9. It is possible that the exclusive northern conformation adopted by these nucleosides reduces their substrate affinity for the various activating kinases, except in the case of the adenosine analogue.

Adenine↗
PubMed2002

Incidence of and risk factors for HIV-associated distal sensory polyneuropathy.

OBJECTIVE: To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects. METHODS: We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported. RESULTS: At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan-Meier estimate of the 1-year incidence of SDSP was 36%. CONCLUSION: Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.

Adult↗
PubMed1988

Genetic analysis of 2',3'-dideoxycytidine incorporation into cultured human T lymphoblasts.

In order to analyze the cellular determinants that mediate the action of 2',3'-dideoxycytidine, the growth inhibitory and cytotoxic effects and the metabolism of the dideoxynucleoside were examined in wild type human CEM T lymphoblasts and in mutant populations of CEM cells that were genetically deficient in either nucleoside transport or deoxycytidine kinase activity. Whereas 2',3'-dideoxycytidine at a concentration of 5 microM inhibited growth of the wild type CEM parental strain by 50%, two nucleoside transport-deficient clones were 4-fold resistant to the pyrimidine analog. The deoxycytidine kinase-deficient cell line was virtually completely resistant to growth inhibition by the dideoxynucleoside at a concentration of 1024 microM. An 80% diminished rate of 2',3'-[5,6-3H]dideoxycytidine influx into the two nucleoside transport-deficient lines could account for their resistance to the dideoxynucleoside, while the resistance of the deoxycytidine kinase-deficient cells to 2',3'-dideoxycytidine toxicity could be explained by a virtually complete failure to incorporate 2',3'-[5,6-3H]dideoxycytidine in situ. Two potent inhibitors of mammalian nucleoside transport, 4-nitrobenzylthioinosine and dipyridamole, mimicked the effects of a genetic deficiency in nucleoside transport with respect to 2',3'-dideoxycytidine toxicity and incorporation. These data indicate that the intracellular metabolism of 2',3'-dideoxycytidine in CEM cells is initiated by the nucleoside transport system and the cellular deoxycytidine kinase activity.

Acquired Immunodeficiency Syndrome↗
PubMed2005

A sheath-flow nanospray interface for capillary electrophoresis/mass spectrometry.

We have developed a novel sheath-flow interface for low-flow electrospray ionization mass spectrometry (ESI-MS) and capillary electrophoresis/electrospray mass spectrometry (CE/ESI-MS). The interface is composed of two capillaries. One is a tapered fused-silica ESI emitter suitable for microliter and nanoliter flow rate electrospray and the other is a tail-end gold-coated CE separation column that is inserted into the emitter. A sheath liquid is supplied between the column and the emitter capillaries. The gold coating and the sheath liquid are used as the conducting media for ESI and the CE circuit. This novel design was initially evaluated by an infusion ESI-MS analysis of the most common antiretroviral dideoxynucleosides, followed by CE/MS coupling analysis of several antidepressant drugs. With infusion studies, the effects of the sheath liquid and the sample flow rates on detection sensitivity and signal stability were investigated. For an emitter with an internal diameter of 30 microm, the optimum flow rates for the sheath and the sample were 200 and 300 nL/min, respectively. The main improvement of this approach in comparison with conventional sheath liquid approaches using an ionspray interface is the gain in sensitivity. Sensitivities were three times better for dideoxynucleosides analyzed by infusion and 12 times higher for antidepressant drugs analyzed by CE/MS with this interface compared with ionspray. The emitter is durable, disposable, and simple to fabricate.

Anti-Retroviral Agents↗
PubMed1989

Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.

A number of 2',3'-dideoxynucleosides have been shown to inhibit the in vitro infectivity and cytopathic effect of the human immunodeficiency virus (HIV). These compounds, as their 5'-triphosphates, inhibit viral reverse transcriptase by competing with the natural substrate at the same binding site on the enzyme. Dideoxynucleoside triphosphates can also be incorporated into growing DNA chains which then blocks further DNA elongation because they lack the 3'-hydroxyl group required for further polymerization. Among these nucleosides, 2', 3'-dideoxyadenosine 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) show promising in vitro activity. Because adenosine is rapidly converted to inosine by adenosine deaminase, the in vivo conversion of ddA to ddI was studied to determine suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of ddA. This report describes and compares the pharmacokinetics of ddA and ddI in the mouse.

Animals↗
PubMed1993

Permeation and metabolism of anti-HIV and endogenous nucleosides in human immune effector cells.

Numerous anti-HIV drugs are synthetic analogs of endogenous nucleosides. Therefore it is of interest to see if a facilitated nucleoside transport system exists to mediate their uptake into human immune effector cells that are known HIV targets. Nucleoside permeation and metabolism in lymphocytes, macrophages and bone marrow cells isolated from healthy human volunteers were studied, using uridine as the prototype endogenous nucleoside. There are saturable broad specificity nucleoside transport systems in all three cell types, all of which were inhibited by dipyridamole. The Vmax and Km values for uridine transport were 0.05 +/- 0.01 pmol/sec/10(6) cells and 18.4 +/- 4.2 microM, respectively, for lymphocytes, 0.04 +/- 0.01 pmol/sec/10(6) cells and 25.3 +/- 6.6 microM, respectively, for macrophages, and 0.03 +/- 0.01 pmol/sec/10(6) cells and 90.2 +/- 10.1 microM, respectively, for bone marrow mononuclear cells. Anti-HIV dideoxynucleosides such as azidothymidine (AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyinosine (DDI), 2',3'-dideoxyadenosine (DDA), and 2',3'-dideoxythymidine (DDT) are not substrates of this nucleotide transport system; hence, little or no drug accumulated inside the cells after 60 sec. Equilibration of cells with uridine or dideoxynucleosides for 2 hr resulted in high levels of cellular uridine and DDA, low levels of cellular AZT, but undetectable levels of the other analogs in all three cell types. Active metabolite levels in lymphocytes as assayed by HPLC correlated with the drug permeation results. Our data demonstrated that DDC, DDI, and DDT are not substrates for the nucleoside transporter and cannot diffuse readily across the cell membrane of human immune effector cells. Future anti-HIV drug development efforts should consider drugs that are substrates of the nucleotide transporter to ensure rapid and complete uptake into target cells.

Biological Transport↗
PubMed1992

Structural analysis of 2',3'-dideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxyguanosine and 2',3'-dideoxycytidine by 500-MHz 1H-NMR spectroscopy and ab-initio molecular orbital calculations.

Solution structure of anti-AIDS drug, 2',3'-dideoxyinosine (ddI) has been assessed by NMR spectroscopy and pseudorotational analysis in conjunction with its analogues: 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG) and 2',3'-dideoxycytidine (ddC). The absence of 3'-hydroxyl groups in these compounds has prompted us to establish the relationship between proton-proton and corresponding endocyclic torsion angles in the 2',3'-dideoxyribofuranose moiety on the basis of five available crystal structures of 2',3'-dideoxynucleosides. A subsequent pseudorotational analysis on ddI (1), ddA (2), ddG (3) and ddC (4) shows that the twist C2'exo-C3'-endo forms of sugar are overwhelmingly preferred (75-80%) over the C2'-endo envelope forms. The phase angles (P) for North and South conformers with the corresponding puckering amplitude (psi m) for ddI (1), ddA (2) and ddG (3) are as follows: PN = 0.1 degrees, PS = 161 degrees and psi m = 34.1 degrees for ddI (1); PN = 1.4 degrees, PS = 160 degrees and psi m = 34.2 degrees for ddA (2) and PN = 2.4 degrees, PS = 163 degrees and psi m = 33.6 degrees for ddG (3). The predominant North conformer of ddC (4) is intermediate between twist C2'-exo-C3'-endo and C3'-endo envelope (P = 10.9 degrees) with a psi m of 34.7 degrees. Note that these preponderant North-sugar structures (approx. 75-80%) found in the solution studies of ddI (1), ddA (2), dG (3) and ddC (4) are not reflected in the X-ray crystal structures of 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine. The constituent sugar residues in both of these crystal structures denosine and 2',3'-dideoxycytidine. The constituent sugar residues in both of these crystal structures are found to be in the South-type geometry (ddA crystalizes in C3'-exo envelope form, while ddC adopts the form intermediate between the C3'-exo envelope and C3'-endo-C4'-exo twist form). This means that X-ray structures of ddA (2) and ddC (4) only represent the minor conformer of the overall pseudorotamer population in solution. An assumption that the structure of the pentofuranose sugar (i.e. P and psi m) participating in conformational equilibrium described by the two-state model remains unchanged at different temperatures has been experimentally validated by assessing five unknown pseudorotational parameters with eight unique observables (3J1'2', 3J1'2", 3J2'3', 3J2'3", 3J2"3', 3J2"3", 3J3'4' and 3J3"4') for 2',3'-dideoxynucleosides.(ABSTRACT TRUNCATED AT 400 WORDS)

Didanosine↗
PubMed1993

Inhibition of HIV-1 replication in cultured cells with phosphorylated dideoxyuridine derivatives encapsulated in immunoliposomes.

Among the 2',3'-dideoxynucleoside 5'-triphosphates containing a physiological base, 2',3'-dideoxyuridine 5'-triphosphate (ddUTP) has been reported to be among the most powerful inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) in cell-free systems. However, in contrast to other dideoxynucleosides, 2',3'-dideoxyuridine (ddU) is inactive in treatment of HIV-infected cells in culture, since it is a poor substrate for cellular nucleoside kinases. This problem cannot be overcome by the use of phosphorylated ddU because such compounds are unable to cross cell membranes. To promote entry and thus bypass the limiting steps of intracellular phosphorylation, we have encapsulated mono- and tri-phosphorylated ddU in liposomes coupled to monoclonal antibodies (immunoliposomes). We investigated antiviral effects in two human T cell lines (MT-4, CEM). We observed that ddU nucleotides remain phosphorylated for several weeks after encapsulation in immunoliposomes, and potent antiviral activity is obtained when these drugs are delivered into infected cells by cell-specific antibodies (ED50 < or = 1 microM on CEM). In contrast, no inhibition was observed with non-targeted liposomes containing phosphorylated ddU, or with empty liposomes, whether targeted or not.

Antiviral Agents↗
PubMed1992

Synthesis and anti-HIV activity of isonucleosides.

A series of isomeric 2',3'-dideoxynucleosides which contains a modified carbohydrate moiety has been prepared. This class of compounds was designed to mimic the activity of known anti-HIV dideoxynucleosides, while imparting enhanced chemical and enzymatic stability. Isonucleosides containing the standard heterocyclic bases (A, C, G, T) were synthesized via nucleophilic addition of the base to an isomeric sugar unit. Modified derivatives were generated by manipulation of the intact isonucleoside. Two of the compound prepared, iso-ddA (1) and iso-ddG (6), exhibit significant and selective anti-HIV activity, as well as beneficial hydrolytic stability.

Antiviral Agents↗
PubMedDate not supplied

Structure-activity relationships of apio nucleosides as potential antiviral agents.

Several types of novel apio nucleosides were synthesized starting from 1,3-dihydroxyacetone and evaluated for antiviral activity. Among compounds tested, amino substituted apio dideoxynucleosides exhibited anti-HBV activity, while thioapio dideoxynucleosides were found to be active against HIV-1. Apio dideoxydidehydro nucleosides showed moderate to potent anti-HCMV activity, but their bioisosteric thioapio dideoxydidehydro nucleosides did not exhibit any significant antiviral activity.

Antiviral Agents↗
PubMed1991

In vitro inhibition of hepatitis B virus replication by 2',3'-dideoxyguanosine, 2',3'-dideoxyinosine, and 3'-azido-2',3'-dideoxythymidine in 2.2.15 (PR) cells.

Hep G2-derived hepatoblastoma cells (2.2.15), which actively produce hepatitis B virus (HBV), were cultured in the presence of 2',3'-dideoxyguanosine (ddG), 2',3'-dideoxyinosine, or 3'-azido-2',3'-dideoxythymidine (AZT). ddG was the most potent agent. It diminished viral replication by up to 95%, as assessed by the amount of episomal HBV DNA, without impairing cellular growth. AZT was the least effective against HBV. Northern blot analysis revealed no apparent difference in the pregenomic viral RNA profile, suggesting that these dideoxynucleosides suppress reverse transcription in the replicative cycle of HBV. The effect of varying the time of drug exposure showed that these agents can suppress HBV replication even when added late in culture. HBV replication in another 2.2.15 cell population of the same lineage was affected by ddG differently, which may enable the investigation of phenotypic or genetic alterations during culture. The present data suggest that some 2',3'-dideoxynucleosides can exert a potent antiviral activity against HBV in vitro, at least under certain circumstances, although the data do not prove that any of these agents have utility in patients with hepatitis.

Blotting, Southern↗
PubMed1991

Targeted therapy of human immunodeficiency virus-related disease.

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2',3'-dideoxynucleosides, to which 3'-azido-2',3'-dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have also been reported to be active against HIV in short-term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV-1 protease inhibitors are notable as possible new therapies for HIV-1-related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long-term drug-related toxicities; emergence of drug-resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure-activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.

Acquired Immunodeficiency Syndrome↗