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

Sabbavarapu, Narayana Murthy; Shavit, Michal; Degani, Yarden; Smolkin, Boris; Belakhov, V. V.; Baasov, Timor

doi:10.1021/acsmedchemlett.6b00006

Cited by 36 publications

(34 citation statements)

References 22 publications

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“…One such approach is the rational modification of aminoglycosides to achieve new structures with higher levels of PTC suppression activity and lower toxicity. 33,34 This approach has led to the generation of new synthetic aminoglycosides, which have been tested in several models of different genetic diseases. 13,19,20 However, none of these compounds has been evaluated for its capacity to re-express inactivated tumor suppressor genes to prevent the proliferation of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…The recent determination of the X-ray structure of the yeast ribosome in the presence of G418 has provided important insight into the binding of aminoglycosides within the A-site, 3 making it possible to develop promising new leads by rational design strategy. 33 The race to develop more potent readthrough inducers has only just begun. We now know more about the mode of action of aminoglycosides, but their specificity for certain nucleotide contexts remains a major obstacle to the development of drugs with a broader range of action.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells

Bidou

Bugaud

Belakhov³

et al. 2017

RNA Biology

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Nonsense mutations, generating premature termination codons (PTCs), account for 10% to 30% of the mutations in tumor suppressor genes. Nonsense translational suppression, induced by small molecules including gentamicin and G418, has been suggested as a potential therapy to counteract the deleterious effects of nonsense mutations in several genetic diseases and cancers. We describe here that NB124, a synthetic aminoglycoside derivative recently developed especially for PTC suppression, strongly induces apoptosis in human tumor cells by promoting high level of PTC readthrough. Using a reporter system, we showed that NB124 suppressed several of the PTCs encountered in tumor suppressor genes, such as the p53 and APC genes. We also showed that NB124 counteracted p53 mRNA degradation by nonsense-mediated decay (NMD). Both PTC suppression and mRNA stabilization contributed to the production of a full-length p53 protein capable of activating p53-dependent genes, thereby specifically promoting high levels of apoptosis. This new-generation aminoglycoside thus outperforms the only clinically available readthrough inducer (gentamicin). These results have important implications for the development of personalised treatments of PTC-dependent diseases and for the development of new drugs modifying translation fidelity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells

Bidou

Bugaud

Belakhov³

et al. 2017

RNA Biology

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“…New pseudotrisaccharide derivatives of aminoglycosides, in addition, have been designed that exhibit enhanced readthrough properties, compared with gentamicin, on mutations underlying the genetic diseases CF, Usher syndrome, and Hurler syndrome [61]. Overall, this approach proved to be convincing in the development of novel safe and efficient compounds useful for the nonsense suppression therapy of various diseases.…”

Section: Aminoglycosidesmentioning

confidence: 99%

Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia

Borgatti

Altamura

Salvatori

et al. 2020

JCM

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Several types of thalassemia (including β039-thalassemia) are caused by nonsense mutations in genes controlling globin production, leading to premature translation termination and mRNA destabilization mediated by the nonsense mediated mRNA decay. Drugs (for instance, aminoglycosides) can be designed to suppress premature translation termination by inducing readthrough (or nonsense suppression) at the premature termination codon. These findings have introduced new hopes for the development of a pharmacologic approach to cure this genetic disease. In the present review, we first summarize the principle and current status of the chemical relief for the expression of functional proteins from genes otherwise unfruitful for the presence of nonsense mutations. Second, we compare data available on readthrough molecules for β0-thalassemia. The examples reported in the review strongly suggest that ribosomal readthrough should be considered as a therapeutic approach for the treatment of β0-thalassemia caused by nonsense mutations. Concluding, the discovery of molecules, exhibiting the property of inducing β-globin, such as readthrough compounds, is of great interest and represents a hope for several patients, whose survival will depend on the possible use of drugs rendering blood transfusion and chelation therapy unnecessary.

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“…. Novel aminoglycosides derived from gentamicin, which showed readthrough activity against four different nonsense DNA constructs underlying genetic diseases, were also recently reported [62]. However, long-term treatment with aminoglycosides showed serious side effects such as nephrotoxicity [63] and ototoxicity [64].…”

Section: Screening Of Readthrough Compoundsmentioning

confidence: 99%

Multidrug Sensitive Yeast Strains, Useful Tools for Chemical Genetics

Chinen¹,

Hamada²,

Taguchi³

et al. 2018

The Yeast Role in Medical Applications

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The budding yeast Saccharomyces cerevisiae is a useful eukaryote model organism for application to chemical biology studies, for example, drug screening, drug evaluation, and target identification. To use yeast for chemical biology research, however, it has been necessary to construct yeast strains suitable for various compounds because of their high drug resistance. Hence, the deletion of all multidrug resistance genes except for those that are important for viability and for genetic experiments/manipulation could increase the drug sensitivity without influencing the transformation, mating, or sporulation efficiency. There are two major factors conferring multidrug resistance in S. cerevisiae: one is the drug efflux system and the other is the permeability barrier. We therefore constructed a strain which shows high sensitivity to multiple drugs by disrupting the drug efflux system using ATP-binding cassette transporters and suppressing the membrane barrier system by introducing an ERG6-inducible system. In this review, we discuss the construction of our multidrug-sensitive yeast strains and their application in chemical biology.

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

Cited by 36 publications

References 22 publications

Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells

Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells

Screening Readthrough Compounds to Suppress Nonsense Mutations: Possible Application to β-Thalassemia

Multidrug Sensitive Yeast Strains, Useful Tools for Chemical Genetics

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