Inhibition of protein synthesis by aminoglycoside???arginine conjugates

Carriere, Marjolaine; Vijayabaskar, V.; Applefield, Drew; Harvey, Isabelle; Garneau, Philippe; Lorsch, Jon R.; Lapidot, Aviva

doi:10.1017/s1355838202029059

Cited by 17 publications

(17 citation statements)

References 49 publications

(32 reference statements)

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“…For discussion, see text. [42]. Broad coverage of antibacterial conjugates obtained from linking various classes of known ribosome-targeted antibiotics has been claimed in a patent application filed by Theravance [252].…”

Section: Other Ribosomal Targets and Ligandsmentioning

confidence: 99%

RNA as a target for small-molecule therapeutics

Hermann¹,

Tor²

2005

Expert Opinion on Therapeutic Patents

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Natural antibiotics that specifically target RNA components of the bacterial ribosome set precedence for RNA-directed small-molecule drugs. Structured domains of functional RNAs in bacteria and viruses have thus attracted attention as targets for the discovery of novel anti-infectives. Whereas a growing number of RNA-directed ligands have been reported in the literature, creating synthetic molecules that combine high affinity with selectivity for a specific RNA target remains a key challenge. Ongoing discovery efforts towards this goal, combined with the increasing knowledge of the factors that govern small-molecule recognition of RNA folds, will prepare the ground for the development of novel RNA-targeted therapeutics.

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Section: Other Ribosomal Targets and Ligandsmentioning

confidence: 99%

RNA as a target for small-molecule therapeutics

Hermann¹,

Tor²

2005

Expert Opinion on Therapeutic Patents

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“…In vitro transcriptions were performed as previously described using BamHI linearized templates. Translations were performed in Krebs extracts as previously reported (Carriere et al 2002). Translations in rabbit reticulocyte lysates, wheat germ extracts, and E. coli S30 extracts were performed as recommended by the manufacturer (Promega Corp).…”

Section: In Vitro Translationsmentioning

confidence: 99%

Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles

Chan¹,

Khan²,

Harvey³

et al. 2004

RNA

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The National Cancer Institute (NCI) Human Tumor Cell Line Anti-Cancer Drug Screen has evaluated the cytotoxicity profiles of a large number of synthetic compounds, natural products, and plant extracts on 60 different cell lines. The data for each compound/extract can be assessed for similarity of cytotoxicity pattern, relative to a given test compound, using an algorithm called COMPARE. In applying a chemical biology approach to better understand the mechanism of eukaryotic protein synthesis, we used these resources to search for novel inhibitors of translation. The cytotoxicity profiles of 31 known protein synthesis inhibitors were used to identify compounds from the NCI database with similar activity profiles. Using this approach, two natural products, phyllanthoside and nagilactone C, were identified and characterized as novel protein synthesis inhibitors. Both compounds are specific for the eukaryotic translation apparatus, function in vivo and in vitro, and interfere with translation elongation. Our results demonstrate the feasibility of utilizing cytotoxicity profiles to identify new inhibitors of translation.

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“…An additional interesting property of AACs (e.g., NeoR6 and R3G) is inhibition of bacterial (and to a lesser extent, mammalian) RNAse P activity ∼500 fold more efficiently than neomycin B [22]. We have recently shown the capacity of several AACs to inhibit peptidyl transferase activity [23].…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

et al. 2004

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We present here a new set of aminoglycoside-arginine conjugates (AACs) that are either site-specific or per-arginine conjugates of paromomycin, neamine, and neomycin B as well as their structure-activity relationships. Their binding constants (K D ) for TAR and RRE RNAs, measured by fluorescence anisotropy, revealed dependence on the number and location of arginines in the different aminoglycoside conjugates. The binding affinity of the per-arginine aminoglycosides to TAR is higher than to RRE, and hexa-arginine neomycin B is the most potent binder (K D = 5 and 23 nM, respectively). The 2D TOCSY NMR spectrum of the TAR monoarginine-neomycin complex reveals binding at the bulge region of TAR.

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Inhibition of protein synthesis by aminoglycoside???arginine conjugates

Abstract: ABSTRACT

Cited by 17 publications

References 49 publications

RNA as a target for small-molecule therapeutics

RNA as a target for small-molecule therapeutics

Eukaryotic protein synthesis inhibitors identified by comparison of cytotoxicity profiles

Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

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