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PubMed1984

Affinity of reverse transcriptase for some polynucleotide inhibitors.

The relative affinity of avian myeloblastosis virus reverse transcriptase for (U)n and a series of (U)n analogs has been measured directly in solution under conditions previously used to demonstrate the inhibitory properties of these polynucleotides. The affinities were measured by electron spin resonance through a quantitative competition approach where the concentration of each polynucleotide required to compete with the macromolecular spin probe (ls4U,U)n for reverse transcriptase was observed. Using this approach the following relative affinities were determined: K(dUfl)n = 1.6K(dUz)n = 13K(dT)n = 20K(U)320-640 = 57K(dU)n = 167K(U)80 greater than 167K(Um)n These results show that the affinity of (U)n for reverse transcriptase is affected by modifying the (U)n matrix and by the molecular weight of (U)n. In addition, the effect of some factors such as Mg+2 and salt on the polynucleotide affinity for the enzyme was measured. The results show that the same binding, i.e., the fraction of saturation F as a function of the nanomoles of reverse transcriptase added, was observed in the presence or absence of Mg+2, whereas increasing the KCl concentration from 0.04 to 0.5M completely dissociates the polynucleotide X enzyme complex.

Avian Myeloblastosis Virus↗
PubMedDate not supplied

Perspectives for the chemotherapy of AIDS.

In the design of selective inhibitors of the human immunodeficiency virus (HIV), the etiologic agent of AIDS, various steps of the virus replicative cycle could be envisaged as targets, i.e. virus adsorption to its cellular receptor (or another early event in virus replication such as penetration or uncoating), transcription of the viral RNA genome to proviral DNA (reverse transcription), trans-activation of viral mRNA transcription and translation, and, finally, virus release ("budding", or another late event in virus replication such as the assembly process). Although some potent HIV inhibitors such as heparin and dextran sulfate may interfere with an early step of the virus replicative cycle (adsorption) and others (interferon and interferon inducers) are assumed to act at a late step (budding), the majority of the anti-HIV agents appear to act at the reverse transcriptase level. Most of these reverse transcriptase inhibitors belong to the class of the 2',3'-dideoxynucleosides (ddN), and within this class of compounds a variety of 2',3'-dideoxy-, 2',3'-didehydro-2',3'-dideoxy-, 3'-azido-2',3'-dideoxy- and 3'-fluoro-2',3'-dideoxyribosides of both purines and pyrimidines have been described as potent and selective anti-HIV agents. Akin to 3'-azido-2',3'-dideoxythymidine (AZT), the sole anti-HIV compound that has so far been licensed for clinical use in the treatment of AIDS, all other ddN analogues are postulated to interact as competitive inhibitors (with respect to the natural substrates) and/or chain terminators of the HIV reverse transcriptase. To do so, the ddN analogues need first to be phosphorylated by cellular kinases to the corresponding 5'-triphosphates (ddNTPs), and together with the affinity of the ddNTPs for the HIV reverse transcriptase (relative to their affinity for the cellular DNA polymerases), the extent by which the ddNs are phosphorylated to the ddNTPs are critical determinants of their potency and selectivity as anti-HIV agents. Much more remains to be learned about the in vivo efficacy of the 2',3'-dideoxynucleoside analogues, and their pharmacokinetic and toxicological properties, before their true potential in the treatment of AIDS can be fully assessed.

Acquired Immunodeficiency Syndrome↗
PubMed1982

Differential inhibition of DNA polymerase and RNase H activities of the reverse transcriptase by phosphonoformate.

Three potential inhibitors of reverse transcriptase activities, phosphonoformate (PF), phosphonoacetate (PAA), and ethyl-diethyl phosphonoformate (Et-PF), were compared in this study. Only PF was found to inhibit the DNA polymerase activity of the purified reverse transcriptase of Moloney murine leukemia virus (M-MuLV) and avian myeloblastosis virus (AMV). The degree of DNA polymerase inhibition was linear with PF concentration; 50% inhibition was achieved at 10 muM. Whereas PF inhibited both the RNA and DNA dependent DNA polymerase activities, the RNase H activity of the reverse transcriptase was unaffected. Both the endogenous DNA polymerase activity in detergent disrupted virus and the activity of the purified enzyme with the isolated virus genome 70S RNA were inhibited by PF. However, higher concentrations of PF were needed to inhibit the endogenous reaction. The inhibition by PF appeared to be reversible and noncompetitive with respect to the substrate deoxythymidine triphosphate (dTTP). Addition of PF after the initiation of DNA synthesis immediately arrested the reaction.

Animals↗
PubMed1983

Retrostatin, a new specific enzyme inhibitor against avian myeloblastosis virus reverse transcriptase.

A novel enzyme inhibitor against RNA-directed DNA polymerase of avian myeloblastosis virus was produced by an isolate of a new streptomycete for which the name Streptomyces retrostaticus is proposed. This enzyme inhibitor, which was named retrostatin, did not inhibit DNA-directed DNA polymerase of Escherichia coli and DNA-directed RNA polymerase of Ehrlich ascites tumor cells. Retrostatin was produced by the microorganism together with streptonigrin. These two substances were extracted from the culture broth with ethyl acetate at acidic pH. Retrostatin is an acidic pH indicator and the free acid was recovered as a red powder. Retrostatin had weak antibiotic activities against Gram-positive bacteria and yeasts.

Animals↗
PubMed1992

[Chemotherapy for human immunodeficiency virus infection. Current status and perspectives].

The role of drugs inhibiting viral replication in patients infected with HIV has been confirmed. Until now only dideoxynucleosides, which are reverse transcriptase inhibitors, have demonstrated antiviral activity in humans. A number of compounds acting on other steps of the viral cycle are currently being evaluated and clinical trials are being performed. Some investigators are attempting to inhibit the binding of viral particles to target cells and their penetration into these by acting on the interaction between HIV ant the CD4 molecule. Another approach consists in the characterization of enzymatic activities which are specific of HIV, other than reverse transcriptase, such as ribonuclease H, integrase or protease, in order to prepare specific inhibitors. Attempts are made to inhibit retroviral gene expression and production of viral particles in infected cells. The development of new nucleoside analogues and drugs with mechanisms of action and toxicities different from those of zidovudine should allow in the near future combination chemotherapy of HIV infection.

Dideoxynucleosides↗
PubMed1979

Suramin: a potent inhibitor of the reverse transcriptase of RNA tumor viruses.

Suramin--a well-known antitrypanosomal agent--was found to exert a strong inhibitory effect on the RNA-directed DNA polymerase (reverse transcriptase) activity of several oncornaviruses such as Moloney murine leukemia virus, murine Rauscher leukemia viruses, Moloney murine sarcoma virus and avian myeloblastosis virus. Inhibition of enzyme activity was obtained with both endogenous viral RNA and (A)n . oligo(dT) as the template-primer. Suramin effected a 50% inhibition of the reverse transcriptase activity of oncornaviruses at a concentration range of 0.1--1 microgram/ml. In this aspect it compared favorably to ethidium bromide, another trypanocide drug which is considered as one of the most powerful inhibitors of oncornaviral DNA polymerases. The inhibition of reverse transcriptase activity by suramin was competitive with the template-primer, (A)n . oligo(dT), suggesting that the drug may interact with the template-primer binding site of the enzyme.

Avian Myeloblastosis Virus↗
PubMed1989

In vivo analysis of castanospermine, a candidate antiretroviral agent.

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), an inhibitor of glycoprotein processing, has been shown to inhibit the human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured cells. In contrast to reverse transcriptase inhibitors, castanospermine targets host enzymes. We have analyzed castanospermine in murine systems, using cultured cells as well as live animals. Plaque formation by Rauscher murine leukemia virus (RLV) was inhibited with a median inhibitory concentration (IC50) of 2 micrograms/ml. RLV-exposed BALB/c mice treated with a 20 day course of castanospermine starting 4 h postinoculation showed a dose-dependent inhibition of splenomegaly. Oral castanospermine therapy given to chronically RLV-infected mice prolonged median survival from 36 to 94 days when compared to untreated controls (p = 0.007). Castanospermine was better tolerated orally than intraperitoneally at the same dose. Toxic effects included weight loss, lethargy, and dose-dependent thrombocytopenia. At the highest intraperitoneal dose, lymphoid depletion occurred in thymus, spleen, and lymph nodes. We conclude that castanospermine is an active antiviral agent in animals and that prolonged oral administration is tolerable; however, when compared to 3'-azido-3'-deoxythymidine in the same murine system, castanospermine was less active and more toxic.

Alkaloids↗
PubMed1985

Observations on the suramin-mediated inhibition of cellular and viral DNA polymerases.

We have examined the sensitivity of various cellular and viral DNA polymerases to Suramin, an antitrypanosomal drug, which has been reported to exhibit antireverse transcriptase activity. We find that Suramin is a nonspecific inhibitor of all the viral and cellular DNA polymerases, including terminal deoxynucleotidyl transferase, and that the inhibition is most readily reversed by the addition of serum albumin. The drug appears to bind to all the enzyme proteins with no apparent selectivity. Binding of Suramin to enzyme has been found to result in the loss of both substrate and templateprimer binding abilities of various enzymes, confirming the nonspecific nature of protein-Suramin interaction.

DNA Nucleotidylexotransferase↗
PubMed1992

Carbohydrates of human immunodeficiency virus.

Elucidation of the mechanism by which viral infection induces the appearance of carbohydrate neoantigens is highly important. Results from such studies could be expected to be significant for a general understanding of the regulation of glycosylation, and perhaps especially important for the understanding of glycosylation in cancer. For anti-viral therapy in AIDS, inhibitors of glycosylation enzymes are very promising as their mode of action may preclude evolvement of resistent HIV substrains, which seems to be a common problem with the reverse transcriptase inhibitors presently used. Successful therapy with glycosylation enzyme inhibitors will, however, require the development of more specific and less toxic compounds. If carbohydrate antigens can elicit a neutralizing immune response in vivo, the possibility exists that carbohydrate neoantigens can be utilized in the construction of a vaccine against AIDS.

Carbohydrate Sequence↗
PubMed1992

The carotenoid halocynthiaxanthin: a novel inhibitor of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2.

We have studied the effects of a natural carotenoid, identified as halocynthiaxanthin, on the enzymatic activities associated with the recombinant preparations of the reverse transcriptases (RTs) of human immunodeficiency viruses (HIV) types 1 and 2. The carotenoid was found to be a potent inhibitor of the RNA-dependent DNA polymerase activity (with 50% inhibition obtained at 5-7 microM halocynthiaxanthin), whereas the DNA-dependent DNA polymerase function of both RTs was significantly less sensitive to the inhibitor. Conversely, the ribonuclease H activity associated with the two HIV RTs was essentially insensitive to the carotenoid. The RNA-dependent DNA polymerase function of RT is the only unique activity found in this enzyme that is not expressed at significant levels in uninfected eukaryotic cells. Therefore, it is possible that this carotenoid may serve as a good candidate for the development of novel potent and specific inhibitors of HIV RT.

Animals↗
PubMed1995

Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes.

The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.

Cell Line↗
PubMed1989

Suramin: an anticancer drug with a unique mechanism of action.

We administered suramin, an anti-parasitic drug and reverse transcriptase inhibitor, to 15 patients with metastatic cancer. This compound is known to inhibit the binding of growth factors (eg, epidermal growth factor [EGF], platelet-derived growth factor [PDGF], tumor growth factor-beta [TGF-beta]) to their receptors and thus antagonize the ability of these factors to stimulate growth of tumor cells in vitro. There were no complete responses (CRs), four partial responses (PRs) (two of ten adrenal cortex, one of four renal, one of one adult T-cell leukemia-lymphoma [HTLV-1]), and two minimal responses (MRs) (two of ten adrenal cortex). Toxicity included proteinuria (14 patients), reversible liver function test abnormalities (eight), vortex keratopathy (five), adrenal insufficiency (three), coagulopathy secondary to increased circulating levels of glycosaminoglycans (11), and one case of a reversible acute demyelinating polyneuropathy resembling the Guillain-Barrè syndrome. We conclude that suramin is an active agent in the treatment of metastatic cancer, and further work is necessary to define its scope.

Adenocarcinoma↗
PubMed1987

Suramin therapy in AIDS and related disorders. Report of the US Suramin Working Group.

Suramin sodium is a reverse transcriptase inhibitor with in vitro activity against the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). Ninety-eight patients with AIDS manifest as opportunistic infections (n = 38), AIDS with Kaposi's sarcoma (n = 38), AIDS-related complex (n = 20), or AIDS-associated non-Hodgkin's lymphoma (NHL) (n = 2) were treated with suramin sodium at 0.5, 1.0, or 1.5 g/wk for six weeks followed by maintenance therapy with 0.5 or 1.0 g/wk. Of 72 patients who were HIV culture positive before therapy and were assessable for subsequent HIV culture 40% became culture negative during treatment, with no apparent correlation between virus recovery and serum suramin concentration. No immunologic improvement was noted. One complete clinical remission was noted in a patient with Kaposi's sarcoma and stage IV NHL. Seven minor clinical responses were also noted. Toxic reactions were generally reversible, and included fever (78%), rash (48%), malaise (43%), nausea (34%), neurologic symptoms (33%), and vomiting (20%). Suramin-induced neutropenia was noted in 26%, thrombocytopenia in 12%, a serum creatinine level of 180 mumol/L or higher (greater than or equal to 2.1 mg/dL) in 12%, liver dysfunction in 14%, and clinical and/or laboratory evidence of adrenal insufficiency in 23%. Sixteen patients died while receiving suramin or within three weeks of discontinuation of drug therapy due to infection (n = 6), hepatic failure (n = 3), pulmonary Kaposi's sarcoma (n = 2), AIDS encephalitis (n = 2), AIDS-associated NHL (n = 1), iatrogenic hemo-pneumothorax (n = 1), or pulmonary disease of uncertain etiology. Suramin as currently administered cannot be recommended as effective therapy for AIDS.

AIDS-Related Complex↗
PubMed1990

Safety and tolerance of dideoxycytidine as a single agent. Results of early-phase studies in patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. Study Group of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

Phase I and II clinical studies have been conducted to test the safety and potential activity of the reverse transcriptase inhibitor, dideoxycytidine (ddC), in treating human immunodeficiency virus-1-infected patients. Although ddC appears to be active in combating viral infection, as judged by its ability to decrease human immunodeficiency virus-1 p24 antigen titers and increase the number of CD4+ lymphocytes, it is also capable of causing severe peripheral neuropathy in a dose-dependent manner. The studies discussed here indicate that low-dose ddC treatment regimens substantially reduce the toxic side effects of this drug, and yet retain the ability to affect p24 antigen and CD4+ lymphocyte levels. These studies also define the window of therapeutic usefulness for ddC, and suggest that both safety and activity can be maintained during long-term, low-dose use of ddC.

AIDS-Related Complex↗
PubMed1990

Dideoxycytidine: current clinical experience and future prospects. A summary.

The reverse transcriptase inhibitor 2',3'-dideoxycytidine (ddC) is capable of mediating virologic and immunologic improvements in some patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. However, severe peripheral neuropathy often develops as a dose-limiting toxicity in ddC-treated patients. Lower doses of ddC may avoid this side effect, while retaining antiviral activity associated with this drug. A series of clinical trials is currently examining regimens employing simultaneous or alternating administration of ddC and 3'-azido-3'-deoxythymidine (zidovudine). Concurrent therapy with more than one drug may allow the use of decreased drug doses and thus reduce dose-dependent toxicities, whereas alternating schedules would provide rest periods from each drug without interrupting therapy. Since zidovudine and ddC possess different toxicity profiles and zidovudine-resistant strains remain susceptible to ddC in vitro, such regimens could theoretically provide additional benefits and reduced toxicity, compared with either agent administered alone. It is hoped that these ongoing and future studies will uncover new and better ways to exploit the therapeutic potential of ddC. However, at present, ddC is an experimental drug and should not be used outside the setting of an approved clinical protocol.

Drug Administration Schedule↗
PubMed1983

Correlation between structure of polyoxotungstates and their inhibitory activity on polymerases.

The 21-tungsto-9-antimonate (TA, HPA 23), a polyoxotungstate, has shown a significant antiviral activity in vivo and in vitro. It inhibits viral and bacterial DNA polymerases. In this paper, several compounds of two polyoxotungstic families, tungstoantimonates and tungstoarsenates, have been used to specify the mechanism of polymerase inhibition. It has been demonstrated that the inhibitory activity of polyoxotungstates is not related to the occupation of their coordinates sites by cations, nor to the nature of these bound cations. Kinetic studies and binding assays have shown that polyoxotungstates bind to the polymerases in competition with the nucleic acid template. This result seems to be related to their polyanionic nature. Furthermore, the size and charge of these compounds may play a prominent part in their affinity for the polymerases.

Antimony↗