HIV reverse-transcriptase

The recent determination of the crystal structure of a ternary catalytic complex of HW-1 RT with a substrate (dTTP) and the DNA-primer and template [121] (Fig. 8) has provided the structured basis of resistance it has been found that most mutations causing resistemce to nucleoside-analog drugs are located closely to the nucleoside binding site. 

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FIGURE 7.3 Diversity of structures that interact with the (a) HIV reverse transcriptase inhibitor binding site [8] and (b) the CCR5 receptor mediating HIV-1 fusion [9],... 

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. 

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

Sodium, potassium ATPase HIV reverse transcriptase Steroid 5a-reductase... 

Figure 3.7 Structure of the HIV reverse transcriptase illustrating the location of the NNRTI binding pocket.

HIV-1 integrase strand transfer inhibitors, 45, 263 HIV prevention strategies, 40, 277 HIV protease inhibitors, 26,141 29, 123 HIV reverse transcriptase inhibitors, 29,123 HIV therapeutics, 40, 291 HIV vaccine, 27, 255... 

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... 

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). 

AZT works by specifically blocking DNA synthesis carried out by HIV reverse transcriptase. Other related compounds are also being tested to see if they specifically affect HIV reverse transcriptase. Such compounds might have equivalent antiviral effects. If they have fewer side effects than AZT, they may be even more effective in treating HIV-infected individuals. Two additional antivirals related to AZT have recently been approved for anti-HIV therapy, dideoxy-inosine (DDI) and dideoxycytosine (DDC). These drugs are predominantly recommended for individuals who cannot tolerate AZT, or for whom AZT has ceased to be effective although they are effective against HIV, they do have side effects. Nevertheless, they may be important because AZT does not indefinitely reduce the amount of virus in HIV-infected individuals. 

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... 

Cross-resistance between indinavir and HIV reverse transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been observed between indinavir and other HIV-protease inhibitors. 

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. 

Metabolism/Excretion Zalcitabine is phosphorylated intracellularly to zalcitabine triphosphate, the active substrate for HIV-reverse transcriptase. Concentrations of zalcitabine triphosphate are too low for quantitation. Metabolism has not been fully evaluated. Zalcitabine does not appear to undergo a significant degree of metabolism by the liver. Renal excretion appears to be the primary route of elimination, and accounted for approximately 70% of an orally administered dose within 24 hours after dosing. The mean elimination half-life is 2 hours. Total body clearance following an IV dose averages 285 mL/min. Less than 10% of a dose... 

The 3-indolylbenzoquinone fragment is a core structure in a number of biologically active natural products such as asterriquinones [49, 50]. The asterriquinones and demethylasterriquinones exhibit a wide spectrum of biological activities, including antitumor properties, and are inhibitors of HIV reverse transcriptase [51-53]. Asterriquinone Al has been shown to stop the cell cycle in G1 and promote apoptotic cell death [54, 55]. Recently, asterriquinone has been reported to be an orally active non-peptidyl mimetic of insulin with antidiabetic activity [56]. The simplest and the most straightforward approach for the synthesis of indol-... 

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