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Reverse transcriptase in HIV

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. [Pg.178]

A practical synthesis of furopyridine (49), a fragment of a HIV-protease inhibitor, was accomplished starting with 6-hydroxynicotinic acid <95TL(36)4571>. Nevirapine (50), and its derivatives, have received much attention because of their inhibition of reverse transcriptase in HIV-type 1 <95JMC(38)4830> <95JMC(38)4839>. (50) has been synthesized using a directed metallation approach <95JOC(60)1875> <95H(41)753>. [Pg.220]

Lamivudine This is a cytosine(cytidine)-nucleoside analogue. Its effect is based on the inhibition of reverse transcriptase in HIV and of DNA polymerase in HBV The daily oral dosage is 1 (-3) x 100 mg/day. After discontinuation of lamivudine, the previous findings recur here, too, efficacy only exists with continued therapy. A combination with famciclovir seems promising. Its clinical application is mainly in combination with IFN. Long-term monotherapy over several years may be necessary. (48,54) (s. p. 704)... [Pg.855]

AZT is an acronym for azidothymidine and is an inhibitor for a pivotal enzyme, reverse transcriptase in HIV-1 virus. Well, let us look at the situation from the ground zero. [Pg.91]

The deterrnination of the presence of reverse transcriptase in vims-infected cells can be done using labeled nucleotide triphosphates. Reverse transcriptase is an enzyme capable of synthesizing DNA from RNA and it is thought to play an important role in vims-mediated cell modification. This enzyme is also a marker enzyme for HIV, the vims impHcated in causing acquired immunodeficiency syndrome (AIDS). The procedure utilizes radiolabeled nucleotides with nonlabeled substrates to synthesize tagged DNA. The degree of radioactive incorporation reflects the reverse transcriptase activity. [Pg.440]

Studies using free energy calculations for the design and analysis of potential drug candidates are reviewed in section five. The chapters in this section cover drug discovery programs targeting fructose 1,6-bisphosphatase (diabetes), COX-2 (inflammation), SRC SH2 domain (osteoporosis and cancer), HIV reverse transcriptase (AIDS), HIV-1 protease (AIDS), thymidylate synthase (cancer), dihydrofolate reductase (cancer) and adenosine deaminase (immunosuppression, myocardial ischemia). [Pg.403]

Divalent metal ions are essential for ribonuclease H activity. Two Mn(II) ions have been located in the catalytic site of ribonuclease H domain of HIV-1 reverse transcriptase in close proximity to the four acidic residues Asp443, Glu478, Asp498, and Asp549 after soaking crystals in 45 mM MnCl2 (406). [Pg.252]

Reverse transcriptase is an RNA-dependent DNA polymerase that requires an RNA template to direct the synthesis of new DNA. Retroviruses, most notably HIV, use this enzyme to repHcate their RNA genomes. DNA synthesis by reverse transcriptase in retroviruses can be inhibited by AZT. ddC, and ddl. [Pg.19]

Initiation of reverse transcription in HIV-infected cells relies on a critical RNA-RNA interaction between tRNA y s, which is preferentially packaged into the viral particle, and a specific viral RNA seqnence. The 3 -terminaI 18 nucleotides of tRNA y are complementary to the primer binding site (PBS) sequence located in the 5 -Iong terminal repeat (LTR) of the viral RNA genome (Figure 10.3). The UUU anticodon of the tRNA is complementary to and binds to an adenosine rich loop located 8 nucleotides upstream (5 ) of the PBS. This RNA-RNA duplex which is formed when tRNA y s binds to the PBS fits within the active site of HIV-1 reverse transcriptase, bnt mnitiple interactions between the viral RNA and tRNA y are necessary for efficient initiation of reverse transcription. This interaction nucleates the reverse transcription complex which contains viral RNA, reverse transcriptase, tRNA y pl , nncleocapsid p7, and Vpr (Viral protein R), as well as multiple host factors." ... [Pg.271]

A) Ritonavir and lopinavir inhibit HIV reverse transcriptase in different ways... [Pg.594]

As an example ddl (2,3-dideoxyinosine), an inhibitor of the HIV reverse transcriptase (RT-HIV), has an only 30-s half-life at pH 1 (at 37°C). Some formulations allow circumventing the problem of the consequent inefficient oral administration. A chemical alternative consists in the introduction of a fluorine atom in 2j] to disfavour the generation of the oxonium ion involved in the proteolysis (Fig. 16) [57,58], Indeed, the fluorinated analogue is stable in acidic medium while keeping the in vitro anti-viral activity. However, it seems that other problems prevented the clinical development [5,57]. [Pg.571]

The pandemic of HIV and the discovery of inhibitors of viral and retroviral enzymes (e.g., AZT, which is an inhibitor of the reverse transcriptase of HIV RT-HIV) have given rise to considerable research. In this connection, deoxynucleosides, which were previously studied as potential antitumor drugs, are receiving renewed attention by researchers. Among these latter compounds, fluorodeoxynucleosides have been the focus of many investigations. ... [Pg.182]

Inhibitors of HIV Reverse Transcriptase (RT-HIV) Replacement of the oxygen by a difluoromethyl in triphosphate analogues of carbovir, is accompanied by a one order-of-magnitude loss in anti-RT activity, while the plasma half-life is fifty times enhanced (Figure 7.19). ... [Pg.237]

The majority of preparations in clinical phases have been found through conventional screening methods and interfere in the inhibition of either reverse transcriptase or HIV protease. The cycle of replication is shown in Figure 13.13. New programs target control and inhibition of all three HIV enzymes, such as reverse transcriptase, protease, and integrase, as well as regulator proteins such as Tat,... [Pg.389]

Experience teaches us that combinations of active compounds offer the most promising perspective - for example, the combination of AZT with 3TC of BioChemPharma (Laval, Quebec, Canada). Currently (2003), there are seven approved entities of nucleoside analogs (NRTIs) and three approved non-nucleosides (NNRTIs) that inhibit reverse transcriptase (RT) by mimicking the structure of DNA building blocks and thus the copy process of RNA into DNA by reverse transcriptase. In addition, five HIV protease inhibitors and one viral fusion inhibitor have been approved. [Pg.390]

All life forms require polymerases for replication of nucleic acids. DNA polymerases from various life forms [8] as well as reverse transcriptase from HIV [9] are all activated by two metal ions, which are thought to provide three types of activation, i.e. Lewis acid, metal-hydroxide and leaving group [Figure 6.26(A)], The Klenow fragment of DNA polymerase I is a 3, 5 -exonuclease that is involved in editing the growing... [Pg.151]

Abacavir is a guanidine analogue that inhibits HIV reverse transcriptase. In vitro, its potency is similar to that of zidovudine, protease inhibitors, and dual nucleoside combinations. There is evidence that abacavir is effective in reducing viral load and increasing the CD4 count in HIV-infected patients. Viral resistance is not rapidly selected for, but cross-resistance has been shown to other analogues of cytosine and guanidine (didanosine, lamivudine, and zalcitabine). [Pg.2]

The HIV virus is a retrovirus, a virus that contains RNA, which it carries into the cell along with an enzyme called reverse transcriptase. The HIV virus uses the reverse transcriptase enzyme to make a DNA copy of the RNA genetic pattern. The DNA segment enters the cell s nucleus, where it becomes a part of the cell s genes. There, it causes the cell to make all of the parts needed to make new viruses. The new viruses assemble and leave the cell to infect new cells. The cell is usually destroyed in the process. [Pg.751]

All of the classical antiretroviral agents are 2. .2 -didcoxy-nucleoside analogues. These compounds. share a common mechanism of action in inhibiting the reverse transcriptase of HIV. Because reverse transcriptase acts early in the viral infection sequence, inhihitors of the enzyme block acute infection of cells but are only weakly active in chronically infected ones. Even though the reverse tran.scripta.se inhihitors share a common mechanism of action, their phamtaeo-logical and toxicological profiles differ dramatically. [Pg.379]

The total synthesis of the calophylium coumarin (-)-calanolide A was accomplished by D.C. Baker and co-workers. This compound attracted considerable attention because it is a potent inhibitor of HIV-1 reverse transcriptase. In order to introduce a formyl group at C8, a regioselective Vilsmeier reaction was employed on a coumarin lactone substrate. [Pg.469]

Interference with assembly of viral coat proteins and viral RNA into new virus particles. Interferons may induce in the ribosomes of the host cells production of enzymes that inhibit translation of viral proteins. Avarol and avarine are thought to interfere with cytoskeletal assembly of virus particles. PROTEASE inhibitors can prevent the release of reverse transcriptase, and HIV-1 proteinase (e.g. saquinavir) are under development or in trial application. [Pg.38]

Adams, J. and Merluzzi, V. J. (1993) Discovery of Nevinipine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, in The Search for Antiviral Drugs, Birkhauser, pp. 45-70. [Pg.12]

Boni, J., Pyra, H., and Schupbach, J. (1996) Sensitive detection and quantification of particle-associated reverse transcriptase in plasma of HIV-1 infected individuals by the product-enhanced reverse transcriptase assay. J. Med. Virol. 49,23-28. [Pg.312]

The tetrasodium salt of carbonylbisphosphonate was originally synthesized by Quimby et al. [76], using hydrolysis of a tetraalkyl dichloromethylenebisphos-phonate in aqueous NaOH. In aqueous solution, the yellow ketone form reversibly converts to its colorless hydrate at acidic pH [76], a process which can be assessed by a combination of 31P-NMR and uv-visible spectroscopy at pH 7, the ketone predominates [93]. The salt moderately inhibits HIV reverse transcriptase in a p24 assay, whereas the parent methylene compound is inactive [64], displays some activity vs the pyrophosphate-dependent phosphofructose kinase of the parasite T. gondii [94] and has found use as a selective inhibitor of PCNA-independent DNA polymerase 6, allowing its enzyme activity to be distinguished from that of DNA polymerase a [95]. [Pg.224]


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See also in sourсe #XX -- [ Pg.271 , Pg.272 ]




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