HIV reverse transcriptase inhibition

How do these NRRIs interact with their final target, the HCV RNA replicase They are phosphorylated to their 5 -triphosphate form, and then inhibit the HCV replicase. As they possess a 3 -hydroxyl function, they may not be considered as obligate chain terminators, but they may act as virtual chain terminators, viz. by steric hindrance exerted by the neighboring 2 -C-methyl and/or 4 -C-azido groups. Similar to their NRTI and NNRTI counterparts in the case of HIV reverse transcriptase, the NRRIs (2 -C-methylnucleosides) interact, upon their phosphorylation to the corresponding 5 -triphosphates, with a region of the HCV RNA replicase (or NS5B RNA-dependent RNA polymerase) that is clearly distinct from the site(s) of interaction of the NNRRIs (Tomei et al. 2005). 

NAKANE H (1991) Differential inhibition of HIV-reverse transcriptase and various DNA polymerases by theaflavins , in Proc of Intern Symp on Tea Sci, 26-29 August, 1991, Shizuoka, Japan, 282-6. 

Thiourea compounds have been observed to inhibit human immunodeficiency virus (HIV) reverse transcriptase, a viral enzyme that is responsible for the reverse transcription of the retroviral RNA to proviral DNA. Phenethylthiazoylthiourea (PETT) compounds were discovered as potent inhibitors of HIV type 1 and display certain structure-activity relationships among various substituents in their structure.199 207 Furthermore, thiourea derivatives have been found to be potent and selective viral inhibitors, antifungal and antibacterial compounds.208 215... 

In addition to drugs such as AZT, other antivirals targeted at reverse transcriptase are also being developed. AZT (and its relatives DDI and DDC) inhibits HIV replication by mimicking normal building blocks of DNA and being selectively incorporated by reverse transcriptase into viral DNA as opposed to cellular DNA. Viral DNA that has incorporated these compounds cannot be completed, and virus replication is aborted. Other compounds have been developed that directly inhibit the activity of HIV reverse transcriptase, with relatively little effect on cellular DNA polymerases. The net effect of these compounds also is to selectively inhibit HIV replication. One class of reverse transcriptase inhibitors currently being tested is referred to as TIBO inhibitors. 

The work that paved the way toward enzymatic inhibition was published in the early 1990s by Wudl and coworkers (Schinazietal., 1993 Friedmanetal., 1993 Sijbesma et al., 1993) and since then studies regarding antiviral activity, mainly HIV-protease inhibition, have been carried out to find active compounds. Up to now, the most effective fullerene derivatives are the trans-2, -dimethy 1-bis-fulleropyrrolidin-ium salt (Fig. 1.4) (Marchesan et al., 2005) and the dendrofullerene reported by Hirsch (Schuster et al., 2000) both of them present an ECJ0 of 0.2pM. Also HIV reverse transcriptase can be inhibited by, -dimcthyl-bis-fulleropyrrolidinium salts (Mashino et al., 2005). The same compounds are also active against acetylcholine esterase (AChE), an enzyme that hydrolyzes a very important neurotransmitter. 

Binds to DNA and prevents separation of the helical strands Affects neuronal transmissions Binds to opiate receptors and blocks pain pathway Acts as central nervous system depressant Inhibits Na/K/ATPase, increases intracellular calcium, and increases ventricular contractibility Blocks the actions of histamine on Hi receptor Blocks ai-adrenergic receptor, resulting in decreased blood pressure Inhibits reuptake of 5-hydroxytryptamine (serotonin) into central nervous system neurons Inhibits cyclooxygenase, inhibition of inflammatory mediators Inhibits replication of viruses or tumor cells Inhibits HIV reverse transcriptase and DNA polymerase Antagonizes histamine effects... 

Pharmacology Tenofovir disoproxil, an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, inhibits the activity of HIV reverse transcriptase. 

Pharmacology Zalcitabine, active against HIV, is a synthetic pyrimidine nucleoside analog of the naturally occurring nucleoside deoxycytidine in which the 3 -hydroxyl group is replaced by hydrogen. Within cells, zalcitabine is converted to the active metabolite, dideoxycytidine 5 -triphosphate (ddCTP), by cellular enzymes. ddCTP inhibits the activity of the HIV-reverse transcriptase both by competing for utilization of the natural substrate, deoxycytidine 5 -triphosphate (dCTP), and by its incorporation into viral DMA. 

Lamivudine is a synthetic cytidine analogue used in the treatment of HIV (see Chapter 51) and HBV. Its activation requires phosphorylation by cellular enzymes. Lamivudine triphosphate competitively inhibits HBV DNA polymerase and HIV reverse transcriptase and causes chain termination. It inhibits the activity of mammalian DNA polymerases with a much lower potency. 

A) Ritonavir and lopinavir inhibit HIV reverse transcriptase in different ways... 

Elvucitabine is in phase III development for therapies of HIV and HBV infections. Its anti-viral activity has been shown to result from inhibition of the HIV reverse transcriptase and HBV DNA polymerase (Fig. 35) [99]. 

Mechanism of Action An antiviral that inhibits HIV reverse transcriptase by viral DNA chain termination. Also inhibits RNA- and DNA-dependent DNA polymerase, an enzyme necessary for HIV replication. Therapeutic Effect Interrupts HIV replication, slowing the progression of HIV infection. 

Mechanism of Action A nucleotide analog that inhibits HIV reverse transcriptase by being incorporated into viral DNA, resulting in DNA chain termination. Therapeutic Effect Slows HIV replication and reduces HIV RNA levels (viral load). Pharmacokinetics Bioavailability in fasted patients is approximately 25%. High-fat meals increase the bioavailability. Protein binding 0J%-12% Excreted in urine. Removed by hemodialysis. Half-life Unknown. 

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49-2). Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis. 

Leucetta microraphis [413]. Taurospongin A (485) is a sulfated acetylenic fatty acid derivative from Hippospongia sp. from Okinawa. It inhibits both DNA polymerase b and HIV reverse transcriptase [414]. 

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. 

Emetine and cephaeline are both potent inhibitors of protein synthesis, inhibiting at the translocation stage. They display antitumour and antiviral as well as antiamoebic activity, but are too toxic for therapeutic use. In recent studies, O-methylpsychotrine has displayed fairly low effects on protein synthesis, but a quite potent ability to curb viral replication through inhibition of HIV-reverse transcriptase. This may give it potential in the treatment of AIDS. 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

The natural product asterriquinone Al (41) and asterriquinone derivatives containing the 3-indolylbenzoquinone structure exhibit a wide spectrum of biological activities, including antitumor properties, inhibition of HIV reverse transcriptase and as an orally active nonpeptidyl mimetic of insulin... 

Tramontane, E. Cheng, Y. C. HIV-1 reverse transcriptase inhibition by a dipyridodia-zepinone derivative BI-RG-587. Biochem. Pharmacol, 1992, 43 1371-1376. 

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