Disease relevance of NEPLANOCIN

• Strikingly, in comparing the therapeutic indices between the paired pre- and post-3'-azido-3'-deoxythymidine (AZT) treatment HIV-1 isolates, DZNep and neplanocin A showed an increase of 3- to 18-fold in their potency against AZT-resistant HIV-1 isolates [1].
• In addition, we show that neplanocin A is a potent inhibitor of vaccinia virus (WR) multiplication in monolayer cultures of mouse L-cells [2].
• We have compared the metabolism and some of the metabolic effects of neplanocin A and synthetic (+/-)-aristeromycin (C-Ado) in murine leukemia L1210 cells in culture [3].
• In vivo, neplanocin A afforded only marginal protection against a lethal infection of mice with vesicular stomatitis virus [4].
• Depending on the cells used, the MIC of neplanocin A for these viruses ranged from 0.01 to 4 micrograms/ml, and depending on the parameter used to assess toxicity for the host cell, the specificity index of neplanocin A ranged from 50 to 4,000 [4].

High impact information on NEPLANOCIN

• In an attempt to correlate mRNA methylation with processing, stably transfected CHO cells expressing augmented levels of bovine prolactin were treated with neplanocin A, an inhibitor of methylation [5].
• Furthermore, neplanocin A competitively inhibited the phosphorylation reaction of adenosine in a cell-free system [6].
• The results indicate that neplanocin A is activated by adenosine kinase [6].
• The role of nicotinamide adenine dinucleotide in the inhibition of bovine liver S-adenosylhomocysteine hydrolase by neplanocin A [7].
• Neplanocin A. Actions on S-adenosylhomocysteine hydrolase and on hormone synthesis by GH4C1 cells [8].

Chemical compound and disease context of NEPLANOCIN

• These observations suggest that neplanocin A was efficiently metabolized to the triphosphate level but that this metabolite was responsible for only a fraction of the observed toxicity [9].
• Neplanocin A inhibition of S-adenosylhomocysteine hydrolase in Alcaligenes faecalis has no effect on growth of the microorganism [10].
• Guanine 7-N-oxide was shown to have synergistic activity in combination with neplanocin A against a rhabdovirus, infectious hematopoietic necrosis virus (IHNV), as reported previously [11].
• The methyltransferase inhibitor Neplanocin A interferes with influenza virus replication by a mechanism different from that of 3-deazaadenosine [12].

Biological context of NEPLANOCIN

• The failure of neplanocin A to be converted to analogs of guanine nucleotides apparently is the result of poor capacity of its monophosphate to serve as a substrate for AMP deaminase; the Vmax for deamination of neplanocin-5'-monophosphate by this enzyme was only 5% of that for C-Ado monophosphate [3].
• Analysis of polyamine levels in neplanocin A-treated cells showed a 3.8-fold decrease in putrescine and a 1.7-fold decrease in spermidine by 24 hr, reflecting a decrease in the cell growth rate in response to neplanocin A rather than a direct effect of S-neplanocylmethionine on the cellular S-adenosylmethionine decarboxylase [13].
• Analogue 4b, which exhibited the best antiviral activity (IC50 = 70 microM) in this acyclic series, is substantially less potent than neplanocin A (IC50 = 0.08 microM) as an antiviral agent [14].
• Following binding of substrates (i.e., adenosine or neplanocin A) or a nonsubstrate (i.e., 3'-deoxyadenosine), the independent domain motion associated with the catalytic domain is essentially abolished [15].
• Two synthetic analogs of neplanocin A, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase, were found in this study to inhibit vaccinia virus replication in murine L929 cells but to have reduced cytotoxicity compared with that of the parent compound [16].

Anatomical context of NEPLANOCIN

• The inhibitory effect of Hcys alone was blocked by preincubation with Ad deaminase or Neplanocin A, a potent inhibitor of SAH hydrolase, suggesting the presence of Ad-bound SAH hydrolase in the synaptic membrane [17].
• Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17) [18].
• Neplanocin A, a novel carbocyclic analog of adenosine, was found to be a mixed type inhibitor of S-adenosylhomocysteine hydrolase of human red blood cells with a Ki of 2 nM and an inactivating constant, Ki, of 3 nM [19].

Associations of NEPLANOCIN with other chemical compounds

• Differences in the metabolism and metabolic effects of the carbocyclic adenosine analogs, neplanocin A and aristeromycin [3].
• When neplanocin A and adenosine were incubated in cell lysates, rapid conversion to neplanocin D and inosine, respectively, were observed, illustrating the affinity of these nucleosides for cellular adenosine deaminase [20].
• Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 11. Molecular dissections of neplanocin A as potential inhibitors of S-adenosylhomocysteine hydrolase [14].
• (SVTOTO virus derived from Toto 1101, like SVSTD, lacks the LMR phenotype.) As was the case with SVLM21, SVMS-65a not only possessed the LMR phenotype but also showed an increased sensitivity to Neplanocin A, a potent inhibitor of S-adenosylhomocysteine (ado hcy) hydrolase [21].
• ATP decrease was not observed after adenosine kinase inhibition and ATP concentration even increased in the presence of 2'-deoxyadenosine, neplanocin A and 5'-iodo-5'-deoxyadenosine [22].

Gene context of NEPLANOCIN

• This selection yielded several variants that were nonresponsive to both TRH- and EGF-induced stretching but were still responsive to stretching induced by several other agents (tetradecanoylphorbol acetate [TPA], butyrate, and Neplanocin A) [23].
• However, by removing the 4'-hydroxymethyl group from neplanocin A, analogs 1 and 2 are no longer substrates for adenosine deaminase and adenosine kinase [20].
• Neplanocin A. A potent inhibitor of S-adenosylhomocysteine hydrolase and of vaccinia virus multiplication in mouse L929 cells [2].
• Fluoroneplanocin A exhibited 2-fold more potent SAH inhibitory activity than the parent neplanocin A [24].
• These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of neplanocin A and that transformation by cellular adenosine kinase mediates its cytotoxic properties [16].

Analytical, diagnostic and therapeutic context of NEPLANOCIN

• This compound was highly toxic to Chinese hamster ovary (CHO) cells; the approximate minimum inhibitory concentration of neplanocin A for inhibition of clone formation was 0.1 microM [9].
• Using the neplanocin A titration technique, it was found that the enzyme concentration in L929 cells remained constant over a 48-h period after refeeding the cultures [25].
• Neplanocin A has cytotoxicity against L5178Y cells in culture and showed a remarkable effect on the life prolongation of mice infected with L1210 leukemia [26].

References