Disease relevance of SPARSOMYCIN

• Tobacco mosaic virus and turnip yellow mosaic virus genome RNAs, which have long (greater than or equal to 69 nucleotides) 5'-terminal leader sequences preceding the AUG initiation codon, can form disome initiation complexes when incubated with a wheat germ extract and sparsomycin [1].
• The effects of two peptidyl-transferase inhibitors, anisomycin and sparsomycin, on ribosomal frameshifting efficiencies and the propagation of yeast double-stranded RNA viruses were examined [2].
• Mutations of two other nucleotide positions in the peptidyl transferase center, C2471 and U2519 (C2452 and U2500 in E. coli), conferred resistance to low concentrations of sparsomycin [3].
• Characterization of sparsomycin resistance in Streptomyces sparsogenes [4].
• The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)[5]

High impact information on SPARSOMYCIN

• Its site of action was investigated by inducing a crosslink between sparsomycin and bacterial, archaeal, and eukaryotic ribosomes complexed with P-site-bound tRNA, on irradiating with low energy ultraviolet light (at 365 nm) [6].
• In contrast, sparsomycin, which inhibits polypeptide chain elongation, does not reduce mRNA methylation [7].
• In the presence of sparsomycin, used to accumulate 80 S initiation complexes, no eIF-4E was observed in the 80 S region [8].
• Sparsomycin contacts primarily a P-site bound substrate, but also extends into the active-site hydrophobic crevice [9].
• Kinetics of inhibition of rabbit reticulocyte peptidyltransferase by anisomycin and sparsomycin [10].

Chemical compound and disease context of SPARSOMYCIN

• A sparsomycin-resistant mutant was isolated for the archaeon Halobacterium salinarium and shown to lack a post-transcriptional modification of U2603 (Escherichia coli numbering U2584), which is a universally conserved uridine base located within the peptidyl transferase loop of 23 S rRNA [11].
• Both lincophenicol (1c) and sparsophenicol (1b) inhibited the binding of the iodophenol analogue of sparsomycin to E. coli ribosomes [12].
• The IC50s of both zidovudine and lopinavir against multidrug resistant HIV-1 in the presence of sparsomycin were similar to those in the absence of sparsomycin [13].
• In addition, sparsomycin did not alter the 50% inhibitory concentration (IC50) of antiretroviral drugs directed against HIV-1 including nucleoside reverse transcriptase inhibitors (lamivudine and stavudine), non-nucleoside reverse transcriptase inhibitor (nevirapine) and protease inhibitors (nelfinavir, amprenavir and indinavir) [13].

Biological context of SPARSOMYCIN

• Introduction of the C2518U mutation into the chromosomal 23 S rRNA gene of wild-type H. halobium rendered cells resistant to sparsomycin, demonstrating that a single nucleotide alteration in the rRNA is sufficient to confer resistance [3].
• Lipophilic analogues of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study [5].
• Structure-activity relationships of sparsomycin and its analogues. Inhibition of peptide bond formation in cell-free systems and of L1210 and bacterial cell growth [14].
• Sparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential [15].
• Pharmacokinetics and toxicology of sparsomycin in beagle dogs [16].

Anatomical context of SPARSOMYCIN

• Three series of sparsomycin analogues were prepared and examined for their ability to inhibit DNA or protein synthesis in bone marrow, P388 lymphocytic leukemia, and P815 mastocytoma cells [17].
• Sparsomycin-induced disaggregation but not detachment of hepatic membrane-bound polyribosomes [18].
• Sparsomycin is a cytotoxic drug exhibiting a broad spectrum of in vitro activity against murine tumors and many tumor cell lines [16].
• Here we report that sparsomycin, a streptococcal metabolite, enhances the replication of HIV-1 in multiple human T cell lines at a concentration of 400 nM [13].

Associations of SPARSOMYCIN with other chemical compounds

• Using 125I-labeled phenol-alanine sparsomycin, an analogue of sparsomycin having higher biological activity than the unmodified antibiotic, we studied the requirements and the characteristics of its interaction with the ribosome [19].
• Considering the reported low affinity of puromycin for bacterial ribosomes, this antibiotic is also a surprisingly good competitor of sparsomycin binding to these particles [19].
• Structure-activity relationships of sparsomycin and its analogues. Octylsparsomycin: the first analogue more active than sparsomycin [20].
• Ribosomes from M. verrucaria contain 60S subunits which are not subject to inhibition by T-2 toxin and are also resistant to certain other drugs such as anisomycin and homoharringtonine, but not sparsomycin or cycloheximide [21].
• The modified ribosomes from the resistant strains were more sensitive to other antibiotics like sparsomycin and chloramphenicol [22].

Gene context of SPARSOMYCIN

• Inhibition of Trypanosoma brucei brucei peptidyl transferase activity by sparsomycin analogs and effects on trypanosome protein synthesis and proliferation [23].

Analytical, diagnostic and therapeutic context of SPARSOMYCIN

• Direct broth assay for sparsomycin and related nucleoside antitumor antibiotics using reversed-phase high-performance liquid chromatography [24].
• Sparsomycin (0.1 micrograms/ml, continuous exposure) was active in 11/46 (24%) human tumor xenografts and in 4/5 of the murine tumors, whereas the colony-forming capacity of four human bone-marrows showed no inhibition, suggesting that this dose level may be the relevant in vitro dose [25].
• In addition to being subject to glomerular filtration, sparsomycin is probably also actively excreted and actively reabsorbed by the renal tubuli [16].
• In addition to wild-type HIV-1, sparsomycin also accelerated the replication of low-fitness, drug-resistant mutants carrying either D30N or L90M within HIV-1 protease, which are frequently found mutations in HIV-1-infected patients on highly active antiretroviral therapy (HAART) [13].

References