Antiviral drugs nucleoside reverse transcriptase inhibitors

DRUGS TO TREAT INFECTIONS ANTIVIRALS - ANTIRETROVIRALS Nucleoside reverse transcriptase inhibitors... 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

The resolution of racemic FTC butyrate (34) was required for the synthesis of the antiviral drug emtricitabine (Emtriva) (Scheme 7.15) a nucleoside reverse transcriptase inhibitor targeted for treatment of human immunodeficiency virus (HIV) and hepatitis infections [35]. The racemic FTC butyrate ester (34) was treated with immobilized cholesterol esterase, which cleaved the required isomer to the corresponding alcohol (-) 35 with 91% and 52% conversion [36]. The product was isolated as the hydrochloride salt to give 31% yield (98% ) from the 8 kg demonstration. The esterase was immobilized by precipitation onto an accurel polypropylene support using acetone followed by cross linking with glutaralde-... 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Secondary drug ANTIVIRALS Effect Mechanism Precautions... 

A sensitive method to measure toxic effects of drugs is to monitor cellular metabolism by incorporation of 3H-thymidine or 14C-protein hydrolysate. 14C-protein is used in preference to 3H-thymidine when it is necessary to avoid competition in uptake between the labeled thymidine and an unlabeled nucleoside reverse-transcriptase inhibitor. These methods are used mainly to monitor sublethal toxicity after initial screening or when comparing structure-activity relationships. The assays described here are carried out using 6-mL culture tubes (Note 1). These assays are carried out in parallel with the antiviral assay. 

Some ofthe classical antiviral drugs in HIV therapy are nucleoside derivatives, and they are called nucleoside reverse transcriptase inhibitors (NRTIs). Zidovudine... 

Lead by Cialis, there are seven indole-containing commercial drugs in the Top-200 Best Selling Drugs by US Retail Sales in 2012. Examples of indole derivatives marketed as antiviral drugs, for example, are Arbidol (a broad-spectrum antiviral with anti-influenza and immunomodu-lating effects) and Delavirine (a non-nucleoside reverse transcriptase inhibitor) [42]. 

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. 

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