Molecular bases for the action and selectivity of nucleoside antibiotics

Carrasco, Luís; Vázquez, David

doi:10.1002/med.2610040403

Cited by 25 publications

(29 citation statements)

References 188 publications

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“…of metabolic processes, including RNA processing, nucleic acid synthesis, protein synthesis, and methylation of tRNA (2,8,29). It was therefore a concern that 7-deaza-2Ј-C-methyl-adenosine may be readily incorporated into RNA and could result in delayed cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…The EC 50 s and CC 50 s were calculated by regression analysis of the viral CPE data and toxicity control data. The CPE results were confirmed using a Neutral Red assay (3) ( Table), except for the herpesvirus data, which are visual CPE results, and human cytomegalovirus data, which are based on a plaque reduction assay (8,9). In vitro BVDV potency determinations were performed as previously described (31).…”

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confidence: 91%

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A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

Olsen

Eldrup

Bartholomew

et al. 2004

Antimicrob Agents Chemother

225

173

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Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2-C-methyl-adenosine and 2-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

Olsen

Eldrup

Bartholomew

et al. 2004

Antimicrob Agents Chemother

225

173

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“…These results stood in contrast to human and mammalian Ado kinases that were more permissive to modifications to the 3′-position, such as 3′-deoxyadenosine or 3′-aminoadenosine, than of modifications to the 2′-position, such as araA and 2′-deoxyadenosine [33,[35][36][37].…”

Section: ′-Positionmentioning

confidence: 99%

Structure–activity relationship for adenosine kinase from Mycobacterium tuberculosis

Long

Shaddix

Moukha-Chafiq

et al. 2008

Biochemical Pharmacology

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Adenosine kinase (Ado kinase) from Mycobacterium tuberculosis is structurally and biochemically unique from other known Ado kinases. This purine salvage enzyme catalyzes the first step in the conversion of the adenosine analog, 2-methyl-Ado (methyl-Ado), into a metabolite with antitubercular activity. Methyl-Ado has provided proof of concept that the purine salvage pathway from M. tuberculosis may be utilized for the development of antitubercular compounds with novel mechanisms of action. In order to utilize this enzyme, it is necessary to understand the topography of the active site to rationally design compounds that are more potent and selective substrates for Ado kinase. A previous structure-activity relationship identified modifications to the base moiety of adenosine (Ado) that result in substrate and inhibitor activity. In an extension of that work, sixtytwo Ado analogs with modifications to the ribofuranosyl moiety, modifications to the base and ribofuranosyl moiety, or modifications to the glycosidic bond position have been analyzed as substrates and inhibitors of M. tuberculosis Ado kinase. A subset of these compounds was further analyzed in human Ado kinase for the sake of comparison. Although no modifications to the ribose moiety resulted in compounds as active as Ado, the best substrates identified were carbocyclic-Ado, 8-aza-carbocyclic-Ado, and 9-[α-L-lyxofuranosyl]-adenine with 38%, 4.3%, and 3.8% of the activity of Ado respectively. The most potent inhibitor identified, 5′-amino-5′-deoxy-Ado, had a K i = 0.8 μM and a competitive mode of inhibition. MIC studies demonstrated that poor substrates could still have potent antitubercular activity.

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“…1) is a disaccharide pyrimidine nucleoside antibiotic produced by Streptomyces vinaceusdrappus and Streptomyces fasciculatis (22). Amicetin has been known for its activity against a number of both Gram-negative and Gram-positive bacteria, particularly Mycobacterium tuberculosis (16,33), and was also found to have effects against herpesvirus 1 and poliovirus (5). Amicetin has been described as a universal antibiotic, exerting effects against microorganisms of different evolutionary origins, including archaea, bacteria, and eukarya (44), by functioning as a peptidyl transferase inhibitor to block protein biosynthesis (41).…”

mentioning

confidence: 99%

Characterization of the Amicetin Biosynthesis Gene Cluster from Streptomyces vinaceusdrappus NRRL 2363 Implicates Two Alternative Strategies for Amide Bond Formation

Zhang

et al. 2012

Appl Environ Microbiol

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ABSTRACTAmicetin, an antibacterial and antiviral agent, belongs to a group of disaccharide nucleoside antibiotics featuring an α-(1→4)-glycoside bond in the disaccharide moiety. In this study, the amicetin biosynthesis gene cluster was cloned fromStreptomyces vinaceusdrappusNRRL 2363 and localized on a 37-kb contiguous DNA region. Heterologous expression of the amicetin biosynthesis gene cluster inStreptomyces lividansTK64 resulted in the production of amicetin and its analogues, thereby confirming the identity of theamigene cluster.In silicosequence analysis revealed that 21 genes were putatively involved in amicetin biosynthesis, including 3 for regulation and transportation, 10 for disaccharide biosynthesis, and 8 for the formation of the amicetin skeleton by the linkage of cytosine,p-aminobenzoic acid (PABA), and the terminal (+)-α-methylserine moieties. The inactivation of the benzoate coenzyme A (benzoate-CoA) ligase geneamiLand theN-acetyltransferase geneamiFled to two mutants that accumulated the same two compounds, cytosamine and 4-acetamido-3-hydroxybenzoic acid. These data indicated that AmiF functioned as an amide synthethase to link cytosine and PABA. The inactivation ofamiR, encoding an acyl-CoA-acyl carrier protein transacylase, resulted in the production of plicacetin and norplicacetin, indicating AmiR to be responsible for attachment of the terminal methylserine moiety to form another amide bond. These findings implicated two alternative strategies for amide bond formation in amicetin biosynthesis.

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Molecular bases for the action and selectivity of nucleoside antibiotics

Cited by 25 publications

References 188 publications

A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

Structure–activity relationship for adenosine kinase from Mycobacterium tuberculosis

Characterization of the Amicetin Biosynthesis Gene Cluster from Streptomyces vinaceusdrappus NRRL 2363 Implicates Two Alternative Strategies for Amide Bond Formation

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