Novel Paromamine Derivatives Exploring Shallow‐Groove Recognition of Ribosomal‐Decoding‐Site RNA.

Simonsen, Klaus B.; Ayida, Benjamin K.; Vourloumis, Dionisios; Takahashi, Masayuki; Winters, Geoffrey C.; Barluenga, Sofía; Qamar, Seema; Shandrick, Sarah; Zhao, Qiang; Hermann, Thomas

doi:10.1002/chin.200306199

Cited by 6 publications

(10 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results obtained were somewhat discouraging: all the tested 6′-modifications resulted in about 1−2-orders of magnitude decrease in inhibition potency, and the C6′-diasteromeric mixture of 4/5 (∼3:1 ratio) was a 6-fold poorer inhibitor than the parent paromamine (IC 50 Pro values of 24 and 3.9 μM, respectively), concluding that the 6′-position plays a pivotal role in bacterial rRNA recognition. 19 Our results in regards to the bacterial ribosome are in agreement with these previously reported data. Thus, even though instead of 6′-diastereomeric mixture reported in the latter study, we used the Pro ) were quantified in coupled transcription/translation assays by using active luciferase detection as previously described by us.…”

supporting

confidence: 94%

“…Pro values of 24 and 3.9 μM, respectively), concluding that the 6′-position plays a pivotal role in bacterial rRNA recognition. 19 Our results in regards to the bacterial ribosome are in agreement with these previously reported data. Thus, even though instead of 6′diastereomeric mixture reported in the latter study, we used the Pro ) were quantified in coupled transcription/translation assays by using active luciferase detection as previously described by us.…”

supporting

confidence: 94%

“…Finally, it is of note that a very similar rational design strategy, but for the bacterial ribosome, has been reported previously by Hermann and co-workers. 19 Using 3D-structure of paromomycin bound to the bacterial decoding-site rRNA and modeling study, this group synthesized a series of C6′modified pseudodisaccharides, including 4 but as an unassigned mixture of C6′ diastereomers, and tested them as inhibitors of bacterial in vitro translation in comparison to paromamine (rings I and II of paromomomycin, containing a primary 6′hydroxyl at ring I). The results obtained were somewhat discouraging: all the tested 6′-modifications resulted in about 1−2-orders of magnitude decrease in inhibition potency, and the C6′-diasteromeric mixture of 4/5 (∼3:1 ratio) was a 6-fold poorer inhibitor than the parent paromamine (IC 50…”

mentioning

confidence: 99%

See 2 more Smart Citations

Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations

Sabbavarapu

Shavit

Degani

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

New pseudotrisaccharide derivatives of aminoglycosides that exploit additional interaction on the shallow groove face of the decoding-site rRNA of eukaryotic ribosome were designed, synthesized and biologically evaluated. Novel lead structures (6 and 7 with an additional 7′-OH), exhibiting enhanced specificity to eukaryotic cytoplasmic ribosome, and superior nonsense mutation suppression activity than those of gentamicin, were discovered. The comparative benefit of new leads was demonstrated in four different nonsense DNA-constructs underling the genetic diseases cystic fibrosis, Usher syndrome, and Hurler syndrome.

show abstract

supporting

confidence: 94%

supporting

confidence: 94%

mentioning

confidence: 99%

See 1 more Smart Citation

Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations

Sabbavarapu

Shavit

Degani

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…Group I Intron 20 µM [202] 79 Paromamine Human A-site >100 µM 203w [203][204][205] 80 Paromomycin A-site 12 µM 1n32 and others [145] 81…”

Section: Number Ligand Targetmentioning

confidence: 99%

Strategies for the Design of Rna-Binding Small Molecules

Aboul‐ela

2009

Future Med. Chem.

View full text Add to dashboard Cite

Bacterial ribosomal RNA is the target of clinically important antibiotics, while biologically important RNAs in viral and eukaryotic genomes present a range of potential drug targets. The physicochemical properties of RNA present difficulties for medicinal chemistry, particularly when oral availability is needed. Peptidic ligands and analysis of their RNA-binding properties are providing insight into RNA recognition. RNA-binding ligands include far more chemical classes than just aminoglycosides. Chemical functionalities from known RNA-binding small molecules are being exploited in fragment- and ligand-based projects. While targeting of RNA for drug design is very challenging, continuing advances in our understanding of the principles of RNA-ligand interaction will be necessary to realize the full potential of this class of targets.

show abstract

“…In the past, our group has extensively used three-dimensional structure data of aminoglycoside decoding-site complexes for the design and synthesis of novel RNA-targeted ligands based on fragments of the natural products (2,21,22,(27)(28)(29). Studies of semisynthetic aminoglycoside mimetics in our laboratory, along with findings published by others (26), have led us to identify 2-deoxystreptamine (2-DOS) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure-Guided Discovery of Novel Aminoglycoside Mimetics as Antibacterial Translation Inhibitors

Zhou

Gregor

Sun

et al. 2005

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.

show abstract

Novel Paromamine Derivatives Exploring Shallow‐Groove Recognition of Ribosomal‐Decoding‐Site RNA.

Cited by 6 publications

References 1 publication

Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations

Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations

Strategies for the Design of Rna-Binding Small Molecules

Structure-Guided Discovery of Novel Aminoglycoside Mimetics as Antibacterial Translation Inhibitors

Contact Info

Product

Resources

About