Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations

Nudelman, Igor; Glikin, Dana; Smolkin, Boris; Hainrichson, Mariana; Belakhov, V. V.; Baasov, Timor

doi:10.1016/j.bmc.2010.03.060

Cited by 117 publications

(136 citation statements)

References 44 publications

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“…Treatment of MB231 cells with G418, a suppressor of translation stop codon, [27][28][29] decreased the abundance of the 40-kD proteins, as detected with sc-601 (lanes 3 vs. 6 in Fig. 2C).…”

Section: Stop Codon Suppression Redistributes Some Putative Cdk4 Isofmentioning

confidence: 69%

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

et al. 2013

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“…Treatment of MB231 cells with G418, a suppressor of translation stop codon, [27][28][29] decreased the abundance of the 40-kD proteins, as detected with sc-601 (lanes 3 vs. 6 in Fig. 2C).…”

Section: Stop Codon Suppression Redistributes Some Putative Cdk4 Isofmentioning

confidence: 69%

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

et al. 2013

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“…S6. † MIC values in E. coli were previously reported (31)(32)(33). ‡ MIC values were calculated from Matt et al (34).…”

Section: Methodsmentioning

confidence: 99%

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

Shalev

Kondo

Kopelyanskiy³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania , affects millions of people worldwide. Aminoglycosides are mostly known as highly potent, broad-spectrum antibiotics that exert their antibacterial activity by selectively targeting the decoding A site of the bacterial ribosome, leading to aberrant protein synthesis. Recently, some aminoglycosides have been clinically approved and are currently used worldwide for the treatment of leishmaniasis; however the molecular details by which aminoglycosides induce their deleterious effect on Leishmaina is still rather obscure. Based on high conservation of the decoding site among all kingdoms, it is assumed that the putative binding site of these agents in Leishmania is the ribosomal A site. However, although recent X-ray crystal structures of the bacterial ribosome in complex with aminoglycosides shed light on the mechanism of aminoglycosides action as antibiotics, no such data are presently available regarding their binding site in Leishmania . We present crystal structures of two different aminoglycoside molecules bound to a model of the Leishmania ribosomal A site: Geneticin (G418), a potent aminoglycoside for the treatment of leishmaniasis at a 2.65-Å resolution, and Apramycin, shown to be a strong binder to the leishmanial ribosome lacking an antileishmanial activity at 1.4-Å resolution. The structural data, coupled with in vitro inhibition measurements on two strains of Leishmania , provide insight as to the source of the difference in inhibitory activity of different Aminoglycosides. The combined structural and physiological data sets the ground for rational design of new, and more specific, aminoglycoside derivatives as potential therapeutic agents against leishmaniasis.

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“…Dietary supplementation of sapropterin, a synthetic form of BH 4 , the cofactor of PAH, is efficacious in a subset of PAH mutations in lowering blood Phe levels (Kure et al 1999;Bernegger and Blau 2002). More recently, a novel set of compounds have been developed specifically targeting nonsense mutations and in vitro studies have shown that these compounds may be of therapeutic benefit in PKU patients carrying nonsense mutations (Howard et al 1996;Barton-Davis et al 1999;Welch et al 2007;Du et al 2009;Nudelman et al 2010;Ho et al 2013). Mutation screening would identify those patients for whom these approaches, including other mutation-specific therapies such as anti-aggregation compounds for p.G46S (Leandro et al 2011), may be applicable.…”

Section: Introductionmentioning

confidence: 99%

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c. 163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified.A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH 4 ), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH 4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH 4 .

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Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations

Cited by 117 publications

References 44 publications

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

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Repairing faulty genes by aminoglycosides: Development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations

Cited by 117 publications

References 44 publications

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G2/M phases of the cell cycle

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G2/M phases of the cell cycle

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Contact Info

Product

Resources

About

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G₂/M phases of the cell cycle