Reverse transcriptase properties

In the context of treating AIDS, there has been recent excitement from the research of anti-HIV properties of gold complexes. Reverse transcriptase (RTase) is an enzyme... 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

Figure 20.18 The central dogma of molecular biology a summary of processes involved inflow of genetic information from DNA to protein. The diagram is a summary of the biochemical processes involved in the flow of genetic information from DNA to protein via RNA intermediates. This concept had to be revised following the discovery of the enzyme, reverse transcriptase, which catalyses information transfer from RNA to DNA (see Chapter 18). It may have to be modified in the future since changes in the fatty acid composition of phospholipids in membranes can modily the properties of proteins, and possibly their functions, independent of the genetic information within the amino acid sequence of the protein (See Chapters 7, 11 and 14).

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-... 

The NRTIs are nucleoside analogues that act as competitive inhibitors of reverse transcriptase. After conversion to the triphosphate form by host cell kinases, these drugs compete with nucleoside triphosphates for access to reverse transcriptase. All NRTIs lack a 3 -hydroxyl group thus, their incorporation into a growing DNA chain results in its termination. These drugs block HIV replication and therefore the infection of new cells, but they have little effect on cells already infected with virus. Combination therapies often include two NRTIs that are analogues of different bases plus a protease inhibitor. The pharmacokinetic properties of the NRTIs are listed in Table 51.2. 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

The Chemistry of Nucleic Acid Biosynthesis Describe three properties common to the reactions catalyzed by DNA polymerase, RNA polymerase, reverse transcriptase, and RNA replicase. How is the enzyme polynucleotide phos-phorylase similar to and different from these three enzymes ... 

Fig. 26-4A) synthesized DNA normally. This finding stimulated an intensive search for new polymerases. Two were found DNA polymerases II (gene pol B)264 and III. Both are present in amounts less than 25% of that of DNA polymerase I.265 266 Both have properties similar to those of polymerase I, but there are important differences. By now DNA polymerases have been isolated from many organisms, many genes have been cloned and many sequences, both of bacterial and eukaryotic polymerases are known. Comparisons of both sequences and three-dimensional structures,266a/b a few of which are shown in Fig. 27-12, suggest that the polymerases belong to at least six families (Table 27-1). These include the RNA-dependent DNA polymerases known as reverse transcriptases as well as some RNA polymerases.267 2681... 

Sugar derivatives that contain double bonds have been developed and used so extensively that they almost certainly constitute the most versatile category of carbohydrate compounds available for use in synthesis. They may be applied both in the synthesis of complex members of the family and of a myriad enantiomerically pure noncarbohydrate compounds—notably, many of interest in medicinal chemistry. Furthermore, some unsaturated sugar derivatives have themselves been found to possess important therapeutic properties. For example, the unnatural L-nucleoside 1 inhibits reverse transcriptase and shows potent and selective anti-AIDS activity,1 and the unsaturated neuraminic acid analogue 2 is the sialidase-inhibitory... 

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... 

Benzodiazepines and 3//-1,5-benzodiazepines are important classes of compounds because of their interesting pharmacological properties. They show anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic, antiinflammatory activity and also potent inhibitor of HIV-1 reverse transcriptase. Besides their biological relevance, benzodiazepines have also found application as dyes for acrylic fibers [163]. 

Figure 5.6 Complementarity between the major MFTA descriptor contributions to activity of the TIBO inhibitors of HIV-1 reverse transcriptase and the molecular properties of the biotarget protein a) atomic charge (Q) and electrostatic potential (EP) (b) atomic van der Waals radius (i ) and molecular surface (c) local lipophilicity (Lg) and molecular lipophilic potential (MLP) - see text for details.

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