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PubMed1992

HIV inhibitors targeted at the reverse transcriptase.

HIV inhibitors targeted at the virus-associated reverse transcriptase (RT) can be divided into two groups, depending on whether they are targeted at the substrate or nonsubstrate binding site. To the first group belong the 2',3'-dideoxynucleosides (i.e., DDC, DDI), 3'-azido-2',3'-dideoxynucleosides (i.e., AZT), 3'-fluoro-2',3'-dideoxynucleosides (i.e., FLT), 2',3'-didehydro-2',3'-dideoxynucleosides (i.e., D4C, D4T) and carbocyclic derivatives thereof (i.e., carbovir), 2'-fluoro-ara-2',3'-dideoxynucleosides, 1,3-dioxolane derivatives (i.e., 2',3'-dideoxyl-3'-thiacytidine), oxetanocin analogues and carbocyclic derivatives thereof (i.e., cyclobut-G) and the 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) derivatives. These compounds need to be phosphorylated intracellularly to their triphosphate forms before they act as competitive inhibitors or alternate substrates (chain terminators) of HIV RT. The second group includes the tetrahydro-imidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)one (TIBO), 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT), dipyrido[3,2-b:2',3'-e]-[1,4]diazepin-6-one (nevirapine) and pyridin-2(1H)one derivatives, which interact as such, noncompetitively, with a specific allosteric binding site of HIV-1 RT. Compounds belonging to the two different groups may give rise to synergism which combined, and, likewise, viral resistance to the compounds may arise through different mutations, depending on the nature of the compounds and the group to which they belong.

Adenine↗
PubMed1992

In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase.

Several newly discovered potent and selective non-nucleoside inhibitors of human immunodeficiency virus-1 reverse transcriptase (RT) are undergoing evaluation in clinical trials. We studied the potential for development of viral resistance to one of the prototype compounds, BI-RG-587, a dipyridodiazepinone derivative. Human immunodeficiency virus-1 resistant to BI-RG-587 emerged after only one cycle of in vitro infection in the presence of the drug. Resistant virus was cross-resistant to the non-nucleoside tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione derivative R82150 but remained susceptible to 2',3'-dideoxynucleosides and phosphonoformate. Both native (virion-associated) and recombinant RT derived from resistant virus were insensitive to BI-RG-587 and R82150. Nucleotide sequence analysis of multiple drug-resistant and -sensitive recombinant RT clones identified a single predicted amino acid change common to all resistant clones (tyrosine-181----cysteine). These studies suggest that the viral resistance to non-nucleoside RT inhibitors may develop in vivo. This possibility should be carefully monitored in clinical trials of these compounds.

Antiviral Agents↗
PubMed1992

Antibiotics from basidiomycetes. XLI. Clavicoronic acid, a novel inhibitor of reverse transcriptases from Clavicorona pyxidata (Pers. ex Fr.) Doty.

A novel inhibitor of RNA-directed DNA-polymerases was isolated from fermentations of Clavicorona pyxidata. Its structure was elucidated by spectroscopic methods. Clavicoronic acid (1) is a noncompetitive inhibitor of avian myeloblastosis virus (Ki 130 microM) and Moloney murine leukemia virus (Ki 68 microM) reverse transcriptases. In permeabilized cells and isolated nucleic DNA- and RNA-synthesis are not affected. Clavicoronic acid markedly inhibits the multiplication of vesicular stomatitis virus in baby hamster kidney cells by interfering with this virus's RNA-directed RNA-polymerase. 1 exhibits no cytotoxic and very weak antimicrobial activities.

Animals↗
PubMed1978

Gliotoxin analogues as inhibitors of reverse transcriptase. 1. Effect of lipophilicity.

The reaction scheme, developed for the synthesis of the gliotoxin analogue 2, was found to be of general applicability for analogues with varying substituents at N(1) and C(2). Analogues 11b-g prepared by this method are inhibitors of reverse transcriptase (RNA-directed DNA polymerase). Their inhibitory activity seems to be related to the lipophilicity of the effector molecules: the most lipophilic compound is the most active inhibitor. The techniques of reversed-phase thin-layer chromatography with silylated, precoated plates as well as reversed-phase high-performance liquid chromatography were used to measure the relative lipophilicities; both techniques gave analogous results.

Anti-Bacterial Agents↗
PubMed1979

Rapid sequence determination of late simian virus 40 16S mRNA leader by using inhibitors of reverse transcriptase.

A method for the determination of the primary structure of spliced mRNA junction and leader sequences is described. By analogy to the DNA sequencing procedure of Sanger et al. [Sanger, F., Nicklen, S. & Coulson, A. R. (1977) Proc. Natl. Acad. Sci USA 74, 5463--5467], we use 2",3'-dideoxynucleoside triphosphates as chain-terminating inhibitors of the reverse transcriptase (RNA-dependent DNA polymerase) reaction. By using specific DNA restriction fragments as primers in combination with this technique, we have determined the sequence of the spliced junction between the body and the leader sequence of the 16S late mRNA of simian virus 40. The method described should be of general utility in mapping spliced mRNA regions for which the corresponding protein sequence (if any) is unknown.

Base Sequence↗
PubMed1992

Rifamycins as inhibitors of retroviral reverse transcriptase from M-MuLV, RAV-2, and HIV-1.

29 Rifamycins were tested for inhibition of Reverse Transcriptase (RT) as potential anti HIV drugs. Two purified commercial enzymes from M-MuLV and RAV-2 were used. Anti-RT activity was also measured on a crude lysate of HIV-1. The results show that some derivatives have interesting levels of activity on isolated M-MuLV and RAV-2 RTs, while they are less active on the RT in the crude HIV-1 lysate. The active derivatives include oximes and hydrazones, alkylaminoderivatives, open ansa-chain derivatives and derivatives carrying a modified nucleoside.

HIV Reverse Transcriptase↗
PubMed1992

Quinolinehydrazones as inhibitors of retroviral reverse transcriptase.

The inhibitory activity of a series of 2- and 4-quinolinehydrazones on retroviral reverse transcriptase has been studied on enzymes from M-MuLV, RAV-2, and on a crude lysate of HIV-1, assuming the first two enzymes as potential models of the third. The highest activity is mainly found in lipophilic, water soluble 4-quinolinehydrazones. The inhibitory activity of these compounds decreases in changing from the M-MuLV to the RAV-2, and HIV-1 enzymes, in this order.

Cell Survival↗
PubMed1992

Non-nucleoside inhibitors of HIV reverse transcriptase: screening successes--clinical failures.

A little less than two years ago, the first report describing non-nucleoside inhibitors of HIV reverse transcriptase (RT) led to the high anticipation that a range of new drugs could soon be available for the treatment of AIDS. The intervening period has given rise to several such agents but recent clinical trial data has indicated this optimism to be premature. This short review seeks to trace the brief history of the drug discovery process and to assess whether there are lessons to be learnt from the episode.

Antiviral Agents↗
PubMed1978

[Molecular biological aspects of oncogenesis caused by RNA tumor viruses (author's transl)].

This article concerns the molecular mechanisms by which RNA tumor viruses, commonly called as oncornaviruses, transfer their genetic information from the genomic RNA (70 s RNA) of the virions to the cellular DNA, leading to neoplastic transformations. The article describes biochemical and serological properties of reverse transcriptase, its role in the life cycle of RNA tumor viruses and broader implications to molecular biology. In this connection, the authors report their own findings on the role of reverse transcriptase in a preleukemic disease, myelofibrosis. This enzyme, discovered in their laboratory, is antigenically closely related to reverse transcriptase of certain primate RNA tumor viruses, and of human leukemic cells. The article also describes the role of reverse transcriptase inhibitors in viral oncogenesis. Of particular interest, is the partially thiolated polycytidylic acid (MPC) which has been developed by the authors, and is known to have a very high binding affinity to the viral reverse transcriptase. The implication of these basic data on the clinical effectivity of MPC in human leukemia, documented in a few cases, has been discussed.

Cell Transformation, Neoplastic↗
PubMed1978

beta-Lapachone, an inhibitor of oncornavirus reverse transcriptase and eukaryotic DNA polymerase-alpha. Inhibitory effect, thiol dependence and specificity.

beta-Lapachone is a naturally occuring compound that can be isolated from a number of tropical trees. It is shown to be a potent inhibitor of reverse transcriptase activity from both avian myeloblastosis virus and Rauscher murine leukaemia virus. In addition, it affects eukaryotic DNA-dependent DNA polymerase-alpha activity: 50% inhibition is reached in 60-min incubation time by about 8 micron beta-lapachone. Enzyme activity is inhibited irrespective of the purity of the enzyme used or of the amount or type of template/primer or substrate present. The inhibitory effect of the drug is only observed in the presence of dithiothreitol. The primary site of action of beta-lapachone appears to be the enzyme protein, as is also borne out by the specificity of its action. Eukaryotic DNA-dependent DNA polymerase-beta, prokaryotic DNA-dependent DNA polymerase I, several other nucleic acid polymerases and some completely unrelated enzymes are not affected. Reverse transcriptase and DNA-dependent DNA polymerase-alpha may be in someway related in possessing similarly exposed '--SH structures' in their active sites. beta-lapachone thus affords a novel means of studying such interrelationships and of further characterizing enzymes.

Animals↗
PubMed1992

Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors.

The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is potently inhibited by a structurally diverse group of nonnucleoside compounds. These include pyridinone derivatives, tetrahydroimadazo[4,5,1-j,k][1,4]-benzodiazepin-2(1H)-one and -thione, and BI-RG-587 (nevirapine). The compounds act noncompetitively, by an unknown mechanism, with respect to template-primer and nucleotide substrates. Despite a high degree of similarity between the HIV-1 and HIV-2 RTs, the HIV-2 enzyme is totally insensitive to these inhibitors. Using a novel method for joining DNA sequences, we have exploited this difference between the two enzymes to identify the regions of the RT that contribute to the compounds' inhibitory activities. The relative in vitro sensitivities of HIV-1/HIV-2 chimeric and site-specific mutant enzymes were determined. Sensitivity to inhibition was largely, though not exclusively, dependent upon the RT region defined by amino acid residues 176 to 190, with specific contributions by residues 181 and 188. The region defined by residues 101 to 106 was found to functionally interact with the domain from 155 to 217. In addition, the functional equivalence of the three inhibitor groups was shown.

Antiviral Agents↗
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↗
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↗