Nucleosides, antiviral analogs

Yao, S. Y., C. E. Cass, and J. D. Young. Transport of the antiviral nucleoside analogs 3 -azido-3 -deoxy-fhymidine and 2, 3 -dideoxycytidine by a recombinant nucleoside transporter (rCNT) expressed in Xenopus laevis oocytes. Mol. Pharmacol. 1996, 50, 388-393. 

L. Fiume, C. Busi, G. Di Stefano, and A. Mattioli, Coupling of antiviral nucleoside analogs to lactosaminated human albumin by using the imidazolides of their phosphoric esters, Anal. Biochem. 272 407-411 (1993). 

Wada S,Tsuda M, SekineT, Cha SH, Kimura M, Kanai Y, Endou H. Rat multispecific organic anion transporter 1 (rOATl) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol ExpTher 2000 294 844-849. 

Indications Respiratory syncytial viral infections Category Antiviral, nucleoside analog Half-life 24 hours... 

In terms of drug disposition, OATl is the most important member of this transport family. Expressed mainly in the kidney tubule cell, OATl is a dicarboxylate exchange protein that is responsible for basolateral uptake of organic anions such as para-aminohippurate (PAH). OATl mediates the excretion of a diverse array of substrates, including environmental toxins. Substrates for this transporter include antibiotics, antiviral nucleoside analogs, and nonsteroidal anti-inflammatory medications. In fact, more than 100 medications and toxic compounds have been found to interact with OATl. 

Problems of drug resistant viruses can emerge during treatment with the well known antiviral nucleoside analogs and new antiviral agents are sought. 

Biological and Medical Importance of Other Nucleotide Analogs Nucleotide Analogs as Chemotherapeutic Agents Antiviral Nucleoside Analogs (Diagram)... 

Herpes simplex viruses are human pathogens that cause oral and ocular lesions (HSV-1) or genital lesions (HSV-2). These viruses code for enzymes with substrate specificities different from those of the host cell. The pyrimidine metabolism of the cell is augmented by a virus-coded deoxythymidine (dThd) kinase (TK). This enzyme has a relatively broad phosphate acceptor specificity which permits the phosphorylation of several antiviral nucleoside analogs, the first step in their activation. These analogs are selective inhibitors of DNA synthesis in virus-infected cells, in part, because they are phosphorylated to their triphosphate derivatives only in infected cells. 

Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, Anderson KS, Johnson KA. Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 2001 276 (44) 40847-57. 

Although the term nucleoside was once limited to the compounds in Table 28.2 and a few others, cunent use is more permissive. Pyrimidine derivatives of D-arabinose, for exfflnple, occur in the free state in certain sponges and are called spongonticleosides. The powerful antiviral drug ribavirin, used to treat hepatitis C and Lassa fever, is a synthetic nucleoside analog in which the base, rather than being a pyrimidine or purine, is a triazole. 

De Clercq E, Descamps J, De Somer P, Holy A (1978) (S)-9-(2,3-Dihydroxypropyl)adenine an ahphatic nucleoside analog with broad-spectrum antiviral activity. Science 5 563-565 De Clercq E, Holy, A (2005) Acyclic nucleoside phosphonates a key class of antiviral drugs. Nature reviews 4 928-940... 

Allenic nucleoside analogs are currently of high interest as cytotoxic and antiviral agents. Prototypes of this class of compounds (Scheme 18.50) are the nucleoside analogs cytallene (154) and adenallene (155), which were developed by Zemlicka [143]. 

C-Acyclic nucleoside analogs of inosine and guanosine 8-[(/ 5)-2,3-dihydroxypropyl]imidazo[l,5-fl]-l,3,5-triazin-4(3//)-ones were synthesized. The route involved the cyclization and rearrangement of 5-acylamino-5-allyl-6-amino-4,5-dihydropyrimidin-4-ones (1122) to 8-allylimidazo[l,5-a]-l,3,5-triazin-4(3//)-ones (1123). Osmium tetroxide hydroxylation gave 1124. None of these analogs showed appreciable antiviral or antitumor cell activity (84NAR263 87MI6). 

The first successful antiviral, acyclovir, is a nucleoside analog, and is effective against herpesvirus infections. The first antiviral drug to be approved for treating HIV, zidovudine (AZT), is also a nucleoside analog. 

As it is evident from the chemical strnctnre, acyclovir looks like a nucleoside analog of gnanosine in side chain of which, instead of the traditional cyclic sugar residue a 2-hydrox-yethoxymethyl acyclic side chain is present. Acyclovir possesses antiviral activity with respect to types 1 and 2 of herpes simplex, shingles vims, Epstein-Barr virus, and cytomegalovirns. 

Pharmacology Ribavirin is a synthetic nucleoside analog. It has antiviral activity in vitro against RSV, influenza A and B viruses, and herpes simplex virus. Pharmacokinetics ... 

HIV infection PO 750 mg (three 250-mg tablets) 3 times a day or 1,250 mg twice a day in combination with nucleoside analogs (enhances antiviral activity). 

S Additional information <5, 7, 11, 25> (<5,7,11 > in the absence of nucleoside diphosphates the enzyme undergoes Mg -dependent stoichiometric autophosphorylation using ATP, GTP or y-thiotriphosphate as phosphate donor, 2 mol phosphate per mol enzyme [12] <25> autophosphorylation and phosphorylation of histone Hl [19] <31> strong preference for d-enantiomers of antiviral nucleotide analogs like ddATP, ddCTP, 3 -deoxy-3 -thymidine, 2 ,3 -didehydro-2 ,3 -dideoxythymidine [50]) [12, 19, 50]... 

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