Nucleotides analogs

However, acyclic nucleotide analogs (acyclic nucleoside phosphonates) have been developed, which carry one phosphonate moiety and require only the two subsequent phosphorylation steps (De Clercq et al. 1978). Independent of virus-encoded kinases, they display a broader spectrum of efficacy. This class comprises important drugs against HIV (tenofovir) and HBV (adefovir, tenofovir), as well as cidofovir, which is approved for use against CMV retinitis, but also displays an exceptionally broad efficacy profile against many herpesviruses, adenovirus, poxviruses, and papillomaviruses (De Clercq and Holy 2005). 

Kaushik N., Talele T.T., Monel R., Palumbo P., Pandey V.N. Destabilization of tRNA3Lys from the primer-binding site of HIV-1 genome by anti-A loop polyamide nucleotide analog. Nucleic Acids Res. 2001 29 5099-5106. 

Kaushik N., Basu A., Pandey V. N. Inhibition of HIV-1 replication by anti-trans-activation responsive polyamide nucleotide analog. Antiviral Res. 2002 56 13-27. 

Myers R. L., Pandey V.N. Anti-TAR polyamide nucleotide analog conjugated with a membrane-permeating peptide inhibits human immunodeficiency virus type 1 production./. Virol. 2002 76 3881-3891. 

FIGURE 2. Competition curves of R(-)-DOI for [ HJketanserin binding to 5-HT2 serotonin receptors in rat frontal cortex membranes in the presence and absence of the guanine nucleotide analog Gpp(NH)p... 

Nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRI) A modified version of a naturally-occurring nucleoside or nucleotide that prevents human immunodeficiency virus (HIV) replication by interfering with the function of the viral reverse transcriptase enzyme. The nucleoside/nucleotide analog causes early termination of the proviral DNA chain. For activity, an NRTI requires three phosphorylation steps once inside the cell, whereas an NtRI has a phosphate group attached and needs only two phosphorylation steps inside the cell for activity. 

A modified version of this protocol, called THIO-ITCHY, includes the random incorporation of a-phosphothioate nucleotide analogs into the parent genes [27,28]. Exonuclease III activity is inhibited at sites of analog incorporation, which relieves the efforts of producing incremental truncation aliquots. In combination with epPCR, the diversity of the fusion libraries created can be further expanded. 

Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, Sweet DH. The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol 1999 56(3) 570-580. 

Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F et al. Multidrug-resistance protein 5 is a multi-specific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci USA 2000 97( 13) 7476-7481. 

Succinylated derivatives of nucleic acids may be prepared by reaction of the anhydride with available —OH groups. The reaction forms relatively stable ester derivatives that create car-boxylates on the nucleotide for further conjugation or modification (Figure 1.83). This method has been used in nucleic acid synthesis (Matteucci and Caruthers, 1980) and to derivatize nucleotide analogs such as AZT (Tadayoni et al., 1993). 

The antagonists of nicotinic acid are 6-aminonicotinamide and, less potent, 3-acetylpyridine and pyridine-3-sulfonic acid (H15, J4). Nicotinamide has also been reported to be effective in experimental cancer (S3). It is supposedly converted to nonphysiological nucleotide analogs of NAD and NADP because it becomes attached to available apo-dehydrogenase the resulting enzyme cannot function in hydrogen and electron-transfer reactions essential to normal cellular metabolism (D7). 

The trCCR experiment has been apphed to study the boimd conformation of a nucleotide analog bound to Elongation Factor Tu [8,23]. Measurements of the CCR-rates /hi ci C2 H2 and /h3 c3 C4 H4 of the C-labelled nucleotide in the presence of its receptor, resulted in an unambiguous determination of the sugar conformation of the nucleotide. 

Pharmacology Adefovir is an acyclic nucleotide analog of adenosine monophosphate. 

Exploration of Bulk Tolerance at ATP Sites. Non-covalent type inhibitors have also been used to study bulk tolerance around the ATP binding sites. In this vein Hampton and co-workers have both synthesized and tested as inhibitors a large number of adenine nucleotide analogs (Figure 2f) to probe the bulk tolerance at a number of positions on the parent compound (28-31) These compounds have been used to study systematically the isoenzyme selectivity of adenylate kinases, hexokinases, thymidine kinases and pyruvate kinases with respect to bulk tolerance at many sites on the ATP molecule. Some of the most isoenzyme specific results were obtained with pyruvate kinase isoenzymes K,L and M using ADP derivatives. Here 3 -0Me-ADP was found to inhibit pyruvate kinase preferentially with a ratio of inhibitory potency of 7.6 6.0 1.0 for the K,M and L isoenzymes, respectively. Another compound, 8-NHEt-ADP, was selective for the M isoenzyme, giving a ratio of 7.1 1.2 1.0 for the M, K and L forms, respectively. 

Inaki Y. Synthetic nucleotide analogs. Prog Polym Sci 1992 17 515-570. 

Adefovir dipivoxii is an orally-administered nucleotide analog reverse transcriptase inhibitor. However it is used for treatment of hepatitis B and failed as a treatment for HIV. 

Hudarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine. Its cytotoxicity is not well understood. It is rapidly dephospho-rylated at the cell membrane level and then rephos-phorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. It inhibits DNA polymerase and DNA primase. It is also incorporated into DNA and RNA. Hudarabine is administered intravenously by infusion over 30-120 min. It is eliminated by renal excretion with a terminal half life 10 hours. Adverse effects include myelosuppres-sion, nausea, vomiting, chills and fever. The number of CD4 positive cells is reduced and the incidence of opportunistic infections is increased. 

Where nucleic acids are concerned, the enhanced hydrophobicity of abiotic polyfluorinated aromatic bases (e.g., tetrafluorobenzene or tetrafluoroindole deoxyribose derivatives) was exploited as an alternative to natural hydrogen bonding to achieve selective and stable nucleic acid base pairing in duplex DNA [85], The DNA replication was examined using polyfluorinated-nucleotide analogs as substrates. A DNA polymerase active site was able to process the polyfluorinated base pairs more effectively than the analogous hydrocarbon pairs, demonstrating hydrophobic selectivity of polyfluorinated bases for other polyfluorinated bases [86]. 

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. 

---