Purine derivatives for their use in the treatment or prevention of diseases due to a nonsense mutation

Abstract

The present invention relates to a purine derivative for use in the treatment of a disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon.

Description

According to another embodiment of the invention, said purine derivative according to the invention is not the dGMP of formula (II) and / or the formula dAMP (III) Said purine derivative according to the invention can be in the form of a pharmaceutically acceptable salt. A pharmaceutically acceptable salt of the purine derivative according to the invention includes acid or base addition salts of said purine derivative. Suitable acid addition salts are formed from acids that form nontoxic salts. Examples of acid addition salts include, but are not limited to, acetate, trifluoroacetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, tetrafluoroborate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, and gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsyllate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, monohydrogenated phosphate, dihydrogenated phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate. Suitable base addition salts are formed from bases that form nontoxic salts.Examples of salts used as additions to a base include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine, and zinc. Preferably, pharmaceutically acceptable salts include hydrochloride / chloride, hydrobromide / bromide, bisulfate / sulfate, nitrate, citrate, and acetate. The said purine derivative according to the invention can be in the form of a solvated. The term "solvated" refers to a purine derivative according to the invention comprising stoichiometric or substoichiometric amounts of one or more molecules of a pharmaceutically acceptable solvent such as ethanol. The term "disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon" refers to a disease caused by the presence of a nonsense mutation affecting a gene of interest in germ cells and / or somatic cells; the nonsense mutation being a point mutation of a codon that results in the change of a codon encoding an amino acid into a UGA stop codon which leads to the cessation of translation. Several diseases caused by this nonsense mutation have been described (Keeling et al., 2006; Bidou et al., 2012; Lee and Dougherty, 2012; Kosuga et al., 2016). These diseases can affect various organs, such as the liver, intestines, kidneys, lungs, muscles, bone marrow, or central nervous system. Diseases caused by a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon can be identified by genotyping methods of the cells of the subject to be treated, particularly by sequencing or by quantifying the expression of the gene of interest. These methods are well known to those skilled in the art (Baharin et al., 2015; Bladen et al., 2015; Cangül et al., 2015; Carmosino et al., 2016; Csânyi et al., 2016; Kosuga et al., 2016; Lin et al., 2016; Roosing et al., 2016; Xia et al., 2016; Zemrani et al., 2016; Zhao et al., 2016). For example, International Application WO 2012 / 016930 generally describes a method for determining whether a disease is due to this nonsense mutation. Diseases caused by said nonsense mutation include inflammatory diseases caused by said nonsense mutation, neurodegenerative diseases caused by said nonsense mutation, autoimmune diseases caused by said nonsense mutation, cardiovascular diseases caused by said nonsense mutation, pulmonary diseases caused by said nonsense mutation, cancers caused by said nonsense mutation, amyloidosis caused by said nonsense mutation, Alzheimer's disease caused by said nonsense mutation, atherosclerosis caused by said nonsense mutation, gigantism caused by said nonsense mutation, dwarfism caused by said nonsense mutation, hypothyroidism caused by said nonsense mutation, hyperthyroidism caused by said nonsense mutation, cystic fibrosis caused by said nonsense mutation, obesity caused by said nonsense mutation, Parkinson's disease caused by said nonsense mutation, and Niemann's disease. Pick due to said nonsensical mutation,familial hypercholesterolemia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, Marfan syndrome due to said nonsense mutation, lysosomal storage diseases due to said nonsense mutation, muscular dystrophies due to said nonsense mutation, hemophilia due to said nonsense mutation, late infantile neuronal ceroid lipofuscinosis due to said nonsense mutation, beta-thalassemia due to said nonsense mutation, Ehlers-Danlos syndrome due to said nonsense mutation, Dravet syndrome due to said nonsense mutation, achromatopsia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, Usher syndrome type IC due to said nonsense mutation, Ehlers-Danlos syndrome type musculocontractural due to said nonsense mutation, the Alagille syndrome due to said nonsense mutation, Alstrôm syndrome due to said nonsense mutation,antithrombin deficiency due to said nonsense mutation, Camey complex due to said nonsense mutation, Currarinon syndrome due to said nonsense mutation, Blackfan-Diamond anemia due to said nonsense mutation, erythropoietic protoporphyria due to said nonsense mutation, Fabry disease due to said nonsense mutation, congenital factor XIII deficiency due to said nonsense mutation, Bickel-Fanconi glycogenosis due to said nonsense mutation, trimethylaminuria due to said nonsense mutation, Gaucher disease due to said nonsense mutation, Rendu-Osler disease due to said nonsense mutation, homocystinuria due to said nonsense mutation, Joubert syndrome due to said nonsense mutation, Krabbe disease due to said nonsense mutation, L-2-HG aciduria due to said mutation nonsense, methylmalonic acidemia due to said nonsense mutation, the syndrome, Peters-plus syndrome due to said nonsense mutation, Townes-Brocks syndrome due to said nonsense mutation, von Willebrand disease due to said nonsense mutation, Wiskott-Aldrich syndrome due to said nonsense mutation, Kabuki syndrome due to said nonsense mutation, Dorfinan-Chanarin disease due to said nonsense mutation, fish eye disease due to a partial deficiency of lecithin-cholesterol acyltransferase due to said nonsense mutation, mucopolysaccharidoses due to said nonsense mutation, coenzyme Q10 deficiency due to said nonsense mutation, Zellweger syndrome due to said nonsense mutation, colorectal cancer due to said nonsense mutation, congenital enteropathy due to enteropeptidase deficiency due to said nonsense mutation, Peutz-Jeghers syndrome due to said mutation nonsense, Jervell and Lange Nielsen syndrome due to said mutation; nonsense, Lynch syndrome due to said mutation; nonsense,microvillus inclusion disease due to said nonsense mutation, xanthinuria due to said nonsense mutation, acidosis due to said nonsense mutation, Alport syndrome due to said nonsense mutation, Bardet-Biedl syndrome due to said nonsense mutation, Birt-Hogg-Dubé syndrome due to said nonsense mutation, Dent disease due to said nonsense mutation, Gitelman syndrome due to said nonsense mutation, hereditary leiomyomatosis-renal cancer syndrome due to said nonsense mutation, Minkowski-Chauffard disease due to said nonsense mutation, Leber congenital amaurosis due to said nonsense mutation, dibasic protein intolerance with lysinuria due to said nonsense mutation, nephronophthisis due to said nonsense mutation, polycystic kidney disease recessive due to said nonsense mutation, pseudohypoaldosteronism due to said nonsense mutation, renal hypoplasia and dysplasia due to said nonsense mutation,clear cell renal cell carcinoma due to said nonsense mutation, papillary renal cell carcinoma type 2 due to said nonsense mutation, Ochoa syndrome due to said nonsense mutation, von Hippel-Lindau disease due to said nonsense mutation, Wilms tumor due to said nonsense mutation, X-linked hypophosphatemic rickets due to said nonsense mutation, juvenile familial hyperuricemic nephropathy due to said nonsense mutation, Boumeville tuberous sclerosis due to said nonsense mutation, Finnish nephrotic syndrome due to said nonsense mutation, corticosteroid-resistant idiopathic nephrotic syndrome, Pierson syndrome due to said nonsense mutation, Denys-Drash syndrome due to said nonsense mutation, Schimke syndrome due to said nonsense mutation, resistance to primary glucocorticoid due to said nonsense mutation, hypophosphatemic vitamin D-resistant rickets due to said nonsense mutation,primary hyperoxaluria type 1 due to said nonsense mutation, pseudohypoaldosteronism type 1 (PHA1) due to said mutation, nonsense, renal tubular acidosis type 2 due to said nonsense mutation, Bassen-Komzweig disease due to said nonsense mutation, Alpers-Huttenlocher syndrome due to said nonsense mutation, carbamoyl phosphate synthase I (CPS1) deficiency due to said nonsense mutation, cholesterol ester storage disease due to said nonsense mutation, citrine deficiency due to said nonsense mutation, Dubin-Johnson syndrome due to said nonsense mutation, factor V deficiency due to said nonsense mutation, glycogen storage disease due to said nonsense mutation, hemophilia due to factor VIII or IX deficiency due to said nonsense mutation, hepatocellular carcinoma due to said nonsense mutation, hepatoeythropoietic porphyria due to said nonsense mutation, familial spastic paraplegia due to said nonsense mutation, ITrypo-betalipoproteinemia due to said nonsense mutation, constitutional factor XI deficiency due to said nonsense mutation,adult-onset diabetes in young people due to said nonsense mutation, microcytic hypochromic anemia due to said nonsense mutation, mitochondrial DNA depletion syndrome due to said nonsense mutation, phenylketonuria due to said nonsense mutation, polycystic liver disease due to said nonsense mutation, porphyria cutanea tarda due to said nonsense mutation, familial progressive intrahepatic cholestasis due to said nonsense mutation, Wilson's disease due to said nonsense mutation, autosomal dominant hypercholesterolemia due to said nonsense mutation, factor XII deficiency due to said nonsense mutation, factor X deficiency due to said nonsense mutation, hypofibrinogenemia due to said nonsense mutation, afibrinogenemia due to said nonsense mutation, factor VII deficiency due to said nonsense mutation, agammaglobulinemia due to said nonsensical mutationAmegakaryocytic thrombocytopenia due to said nonsense mutation, congenital dyserythropoietic anemia type 2 due to said nonsense mutation, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) due to said nonsense mutation, centronuclear myopathies due to said nonsense mutation, limb-girdle muscular dystrophies due to said nonsense mutation, Miyoshi myopathy due to said nonsense mutation, Ullrich congenital muscular dystrophy due to said nonsense mutation, spinal muscular atrophy due to said nonsense mutation, dystrophic epidermolysis bullosa due to said nonsense mutation, Hailey-Hailey disease due to said nonsense mutation, Herlitz junctional epidermolysis bullosa due to said nonsense mutation, Netherton syndrome due to said mutation nonsense, Hurler syndrome due to said nonsense mutation, LINCL (Late Infantile Neuronal Ceroid Lipofuscinosis) due to said nonsense mutation,preferably lung cancer and cystic fibrosis due to the aforementioned nonsense mutation. The present invention also relates to a pharmaceutical composition comprising a purine derivative as defined above, preferably DAP, and a pharmaceutically acceptable excipient for its use (intended to be used) in the treatment of a disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon, as defined above. The term "excipient" means a substance which carries the purine derivative according to the invention in a composition which gives it, for example, properties of stability, form (e.g. liquid, solid, capsule), taste, solubility (e.g. targeted solubility in the stomach or digestive tract) and color. A "pharmaceutically acceptable excipient" is one that does not produce an adverse, allergic, or undesirable reaction when administered to a subject. This includes all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic agents, delayed-absorption agents, and other similar substances. For administration to humans, preparations must meet the criteria for sterility, pyrogenicity, and the general safety and purity standards required by regulatory bodies. The excipient may, for example, be water. The present invention also relates to the use of at least one purine derivative or pharmaceutical composition as defined above for the preparation of a drug intended for the treatment of a disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon as defined above. The present invention also relates to a method for treating a disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon as defined above, comprising administering a therapeutically effective amount of at least one purine derivative or pharmaceutical composition as defined above to a subject in need of such treatment. The terms "treatment" or "treat" refer to both therapeutic treatment and prophylactic or preventive measures, the purpose of which is to prevent or slow the progression of disease caused by a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon. Individuals requiring treatment include those already suffering from disease caused by a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon, those predisposed to disease caused by a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon, and those in whom disease caused by a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon must be prevented. A subject is considered successfully treated for a disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon if, after receiving a therapeutically effective amount of a purine derivative or a pharmaceutical composition according to the invention, the subject shows an observable or measurable reduction, or the absence, of at least one of the following: a reduction in the number of pathogenic cells, a reduction in the percentage of pathogenic cells relative to total cells, and / or an improvement in one or more of the symptoms associated with the disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon, or an improvement in quality of life. The above evaluation parameters are readily measurable by routine procedures familiar to a physician. Advantageously, patients are pre-selected as having said nonsense mutation in a gene of interest. The term "subject" refers to a mammal, preferably a human. In a preferred embodiment, the subject may be a "patient", i.e. a warm-blooded animal, preferably a human, awaiting or receiving medical care, having undergone a medical procedure, or being monitored for the development of a genetic disease linked to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon. A "therapeutically effective amount" refers to the amount of purine derivative or pharmaceutical composition necessary and sufficient to, without causing significant and adverse side effects for the subject, decrease or stop the progression, or aggravation of one or more of the symptoms of the disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon, to relieve the symptoms of the disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon, and / or to cure the disease due to a nonsense mutation of a gene leading to the premature introduction of a UGA stop codon. The methods and routes of administration of the purine derivative or pharmaceutical composition as defined above can be adapted by those skilled in the art depending on the patient and the purine derivative used. For example, the purine derivative according to the invention can be formulated for oral or nasal administration, or for intravenous, intramuscular, or subcutaneous injection, preferably orally. The determination of the dose at which said purine derivative according to the invention is used can be carried out by techniques known to a person skilled in the art, for example during clinical trials. This dose will depend on various factors including in particular the activity of the purine derivative according to the invention, the method of administration, the duration of administration, the duration of treatment, other drugs or compounds used in combination with said purine derivative according to the invention, the age, sex, weight, general health and prior medical history of the subject being treated. According to an advantageous embodiment, the purine derivative according to the invention is administered to a subject in combination with a compound having a reading activity selected from the group consisting of the alpha anomer of cititocin (6-amino-5-nitro-4-(α-D-ribofuranosylamino)-pyrimidine), the beta anomer of cititocin (6-amino-5-nitro-4-(PD-ribofuranosylamino)-pyrimidine), ataluren, gentamicin, geneticin, paromomycin and paromomycin derivatives such as NB30; NB54; NB74; NB84, amikacin, tobramycin, pyramicin and pyramycin derivatives such as TC001; TC003; TC007; TC032, kanamycin and kanamycin derivatives such as JL022;JL023, amlexanox, RTC 13 (Lavin, 2013), RTC 14 (Lavin, 2013), 3-(2-4E(l,l dimethyl propyl)-phenoxy-acetylamino)-benzoic acid, 3-(2-(4-isopropyl-3-methyl-phenoxy)-acetylamino)-benzoic acid, negamycin, tylosin, josamycin, spiramycin, and 3-(2-(4-tert-butyl-phenoxy)-acetylamino)-benzoic acid, preferably selected from the group consisting of the alpha anomer of citrate (6-amino-5-nitro-4-(α-ribofuranosylamino)-pyrimidine), the beta anomer of citrate (6-amino-5-nitro-4“(pD-ribofuranosylamino)-pyrimidine) and ataluren.; The present invention also relates to a composition comprising at least one purine derivative according to the invention, preferably DAP, and a compound having readthrough activity selected from the group consisting of the alpha anomer of citiocin (6-amino-5-nitro-4-(α-D-ribofuranosylamino)-pyrimidine), the beta anomer of citiocin (6-amino-5-nitro-4-(PD-ribofuranosylamino)-pyrimidine), ataluren, gentamicin, geneticin, paromomycin and paromomycin derivatives such as NB30; NB54; NB74; NB84, amikacin, tobramycin, pyramicin and pyramycin derivatives such as TC001; TC003; TC007; TC032, kanamycin and kanamycin derivatives such as JL022;JL023, amlexanox, RTC 13 (Lavin, 2013), RTC 14 (Lavin, 2013), 3-(2-4E(1,1-dimethylpropyl)-phenoxy-acetylamino)-benzoic acid, 3-(2-(4-isopropyl-3-methyl-phenoxy)-acetylamino)-benzoic acid, negamycin, tylosin, josamycin, spiramycin, and 3-(2-(4-tert-butyl-phenoxy)-acetylamino)-benzoic acid, preferably selected from the group consisting of the alpha anomer of cititocin (6-amino-5-nitro-4-(α-ribofuranosylamino)-pyrimidine), the beta anomer of cititocin (6-amino-5-nitro-4-(PD-; ribofuranosylamino)-pyrimidine) and ataluren, for their simultaneous, separate or sequential use for the treatment of a disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon as defined above. In addition to the foregoing provisions, the invention also includes other non-limiting provisions, which will become apparent from the experimental examples below, as well as the accompanying figures: Figure 1: Identification of DAP as a UGA nonsense mutation corrector by screening. A. Measurement of luciferase activity in human HeLa cells expressing a luciferase gene carrying a premature stop codon UAA, UAG, or UGA cultured in the presence of G418 (25 pM, 2400 pM), PTC124 (ataluren) (25 pM), DAP (25 pM), 6-mercaptopurine (25 pM), 2-mercaptopurine (25 pM), or DMSO as a negative control. DAP at 25 pM shows UGA nonsense mutation correction more than three times more effective than G418 at 2400 pM and eighteen times more effective than G418 at 25 pM under these experimental conditions. In this model, ataluren is ineffective at 25 pM. Derivatives of DAP (2-mercaptopurine or 6-mercaptopurine) do not possess nonsense mutation correction activity. B.Luciferase activity was measured in HeLa cells expressing a luciferase gene with a nonsense UGA mutation in the presence of increasing concentrations of DAP or G418 (0.39 pM to 2400 pM), or DMSO (negative control). The values ​​shown represent the average of two dose / response curves for each treatment, and the error bars correspond to the calculation of the standard deviation. Figure 2: Western blot analysis of the re-expression of the TP53 gene carrying a nonsense mutation. A. DAP dose / response experiment and comparison with G418. Proteins from Calu-6 cells (carrying a UGA nonsense mutation at codon 196 in the TP53 gene) cultured in the presence of increasing concentrations of DAP (0.39 pM to 600 pM), G418 (600 pM), or DMSO as a negative control were purified and analyzed by Western blot for the p53 protein. When these cells were incubated in the presence of DMSO, TP53 gene expression was not detectable by Western blot due to the presence of the nonsense mutation. In the presence of DAP, the wild-type p53 protein (p53 FL: p53 full length) is detected from 6.25pM and reaches maximum production at 25 pM.The use of G418 at 600 pM allows the synthesis of an amount of p53 protein identical to that observed with DAP at 6.25 pM and a greater amount of truncated p53 protein (p53 TR), the synthesis of which is halted at the nonsense mutation. B. Analysis of the effect of DAP or G418 on Caco-2 cells carrying a UAG mutation at codon 204 of the TP53 gene. DAP does not allow the re-expression of the p53 protein, unlike [the other protein]. G418. C. Analysis of the effect of DAP or G418 on Caov-3 cells carrying a U AA nonsense mutation at codon 136 of the TP53 gene. DAP does not allow re-expression of the p53 protein, unlike G418, which allows very weak re-expression. In all experiments, the CBP80 protein is used as a loading control, and the three leftmost lanes represent serial dilutions of a HeLa cell extract expressing wild-type p53 protein. Figure 3: Effect of DAP on the phenotype of cultured cells. White light photograph of Calu-6 cells cultured in the presence of increasing concentrations of DAP (0.39 pM to 600 pM), G418 (600 pM), or DMSO as a negative control. Image acquisition was performed using a ZEISS Axiovert 40C microscope at 5x magnification. Figure 4: Measurement of DAP cellular toxicity. Calu-6 cells were cultured in the presence of DAP (6.25 pM, 25 pM), G418 (600 pM), and DMSO (negative control) for 10 days. Cells were initially seeded at a density of 50,000 cells per well (Day 0). Cell counting (A) and apoptosis rate measurement (B) were performed under each condition on Days 4, 6, 8, and 10. Figure 5: DAP does not inhibit NMD. Calu-6 cells are cultured for 24 hours in the presence of DAP (6.25 pM or 25 pM), G418 (600 pM), and DMSO (negative control). RNA from Calu-6 cells is extracted and subjected to RT-PCR in the presence of a radiolabeled nucleotide to quantify the levels of amplified p53 mRNA and GAPDH (as a load control). The three leftmost lanes represent a series of RT dilutions from HeLa cell mRNA. A histogram representation is shown on the right. *: p<0.05. Figure 6. Measurement of the expression of two p53 target genes, p21 and Noxa, in Calu-6 cells after culture in the presence of DAP (6.25 pM or 25 pM), G418 (600 pM), or DMSO (negative control). RNAs from cultured Calu-6 cells were purified, reverse-transcribed, and amplified by PCR, then gel-spotted to assess their levels relative to GAPDH (A). The graphs represent the ratio of p21 (B) and Noxa (C) mRNA expression levels to GAPDH under the different culture conditions. In the presence of DAP or G418, the levels of p53 target gene mRNAs increased, reflecting the synthesis of a functional p53 protein in these cells, unlike the DMSO treatment. Figure 7: Table showing the list of purine derivatives according to the present invention. EXAMPLES 1. Identification of 2,6-diaminopurine (DAP) as a UGA nonsense mutation corrector To identify molecules capable of efficiently correcting nonsense mutations in human cells, the gene encoding firefly luciferase was modified by introducing an intron between codons 448 and 449 of the open reading frame, thus making luciferase expression splicing-dependent, which is the case for more than 90% of human genes. A premature stop codon (TAA, TAG, or TGA) was then inserted in place of codon 109, a position that leads to the activation of nonsense-mediated mRNA decay (NMD) on this mRNA. This recreated an expression context for a spliced ​​gene subjected to NMD, as is the case for the vast majority of genes in human cells when they carry a nonsense mutation. The position of the premature stop codon is such that if protein synthesis stops at the premature stop codon, the truncated luciferase protein synthesized is not functional.Luciferase activity will therefore be measured to be greater than background noise when the luciferase mRNA undergoes readthrough at its premature stop codon, and the intensity of the activity is directly related to the amount of functional luciferase synthesized, and therefore readthrough. For this purpose, HeLa cells were transfected with a luciferase construct carrying one of three nonsense mutations (UAA, UAG, and UGA) using lipofectamine 3000 according to the manufacturer's protocol (Lifetechnologies). The following day, the cells were plated into 96-well plates, and the chemical molecules to be tested were added immediately before a 24-hour incubation. DAP, 6-mercaptopurine, 2-mercaptopurine, and ataluren (PTC124) were added at a concentration of 25 pM. G418 was added at concentrations of 25 pM and 2400 pM. DMSO served as the negative control. SteadyLite Plus substrate (Perkin Elmer) was then added to the culture medium, and the plates were read using a Tristar luminometer (Berthold). Each well was read for 10 seconds, and the plate was read twice. Using these constructs, 2,6-diaminopurine (DAP) was identified as a molecule capable of correcting UGA stop codons much more efficiently than G418 or ataluren (PTC 124), which showed no correction activity at this concentration and in this study model. However, DAP had no effect on UAG or UAA codons, making it an exclusive corrector of UGA mutations (Figure IA). Two DAP derivatives were also tested (2-mercaptopurine and 6-mercaptopurine) but showed no nonsense mutation correction activity. A dose-response curve is shown in Figure IB for DAP and G418 at concentrations ranging from 0.39 pM to 2400 pM to illustrate the difference in efficacy between the two molecules for correcting a UGA nonsense mutation. DMSO represents the negative control. Both molecules begin to significantly correct the nonsense mutation starting at 6.25 pM. At this concentration, DAP induces a correction five times greater than G418 in this model. It is worth noting that DAP does not reach its maximum correction efficacy even at 2400 pM, unlike G418, which reaches it at 1200 pM under these experimental conditions. At 2400 pM (2000 pg / ml), the correction of the UGA nonsense mutation by DAP is more than 18 times greater than that obtained by G418 and at this concentration, G418 is very toxic (see Figure 4). 2. Identification of DAP as a UGA nonsense mutation corrector by transreading. In order to validate the results of the above screen, the correction of nonsense mutations was measured for endogenous genes carrying nonsense mutations in a Calu-6 lung cancer cell line (ATCC, USA) including a UGA mutation in codon 196 of the TPS3 gene (Figure 2A), a Caco-2 cell line carrying a UAG mutation at codon 204 (Figure 2B) and a Caov-3 cell line carrying a UAA nonsense mutation at codon 136 (Figure 2C). These cells were cultured in the presence of increasing concentrations of DAP (0.39 pM; 0.78 pM; 1.56 pM; 6.25 pM; 25 pM; 100 pM; 600 pM), G418 (600 pM), or DMSO as a negative control for 20 hours. The presence of the truncated (p53 TR) and full-length (FL) forms of the p53 protein was detected by Western blot. Proteins were extracted from the cells in lysis buffer and then analyzed by 10% SDS-PAGE as previously described in Gonzalez-Hilarion et al. (2012). Briefly, after migration, the proteins were transferred to a nitrocellulose membrane and incubated with an anti-p53 antibody (D01; Santa Cruz), followed by an anti-mouse secondary antibody (Jackson Immuno Research). The proteins were finally revealed using the SuperSignal West Femto Maximum Sensitivity substrate. The results (Figure 2) show that DAP is able to restore the expression of genes carrying UGA-type nonsense mutations, thus validating the result of the screen. The minimum concentration allowing this re-expression on these lines is 6.25 pM, at which the amount of protein synthesized is similar to the amount obtained with G418 at a concentration of 600 pM, which is a concentration generally used for to demonstrate transreading by G418 (Bidou et al., 2004). At 25 pM of DAP, a greater synthesis of translucent protein is achieved than with G418. 3. DAP shows little or no toxicity at concentrations that allow for the correction of VGA mutations Calu-6 cells treated with DAP or G418 at different concentrations as previously described are observed under a white light microscope (5x magnification) to visualize phenotypic changes in the cells. The results are shown in Figure 3. Up to 25 pM DAP, the cell phenotype is similar to that of cells exposed to DMSO. From 600 pM DAP onward, more dying cells (round appearance) are observed, representing a situation very similar to that observed when incubating cells with G418 at a concentration of 600 pM. This result suggests that under these experimental conditions, DAP is not or only slightly toxic at concentrations of 6.25 pM or 25 pM, concentrations sufficient to obtain readthrough of the premature UGA stop codons (Figure 2). 4. Cell growth and measurement of apoptosis To further investigate the toxicity of DAP, the growth of Calu-6 cells was monitored in the absence or presence of DAP or G418. 50,000 Calu-6 cells were seeded in 6-well plates in the presence of DAP (6.25 pM or 25 pM), G418 (600 pM), or DMSO as a negative control. Every 48 hours, for each treatment condition, cells were retrieved after trypsin digestion and counted using a TALI cytometer (Lifetechnologies), then analyzed for apoptosis as previously described in Jia et al., 2015. Bilaterally, cells were detached from their support using trypsin and then centrifuged for 5 minutes at 200 g. The cell pellet was then lysed and processed to detect apoptotic cells using the Tali® Apoptosis Kit - Annexin V Alexa Fluor® 488 & Propidium lodide (Invitrogen). The results are shown in Figure 4. Unlike cells treated with G418, cells treated with both concentrations of DAP showed a consistently positive growth rate despite a slowdown in growth, particularly at 25 pM (Figure 4A). This result indicates that the number of dividing cells is greater than the number of cells in cell cycle arrest or dead. Moreover, unlike wells cultured in the presence of G418, where the percentage of apoptotic cells rises to more than 30% from the 4th day of culture, in wells treated with DAP, the rate does not exceed 15% (Figure 4B). These results show that DAP induces a slight slowing of the cell cycle but no significant toxicity. 5. DAP does not induce inhibition of NMD To investigate how DAP corrects UGA nonsense mutations, it was determined whether this molecule could inhibit NMD. The level of an mRNA carrying a UGA nonsense mutation (p53 mRNA in Calu-6 cells) was measured in the absence and presence of DAP. Calu-6 cells were cultured in the presence of DAP (6.25 pM or 25 pM), G418 (600 pM), or DMSO as a negative control for 24 hours. RNA was purified with RNazol (MRC) and subjected to RT-PCR as described in Gonzalez-Hilarion et al. (2012). The resulting cDNAs were then amplified after 35 PCR cycles using the following primers: p53 forward (5'-ATTGCTCAAGACTGGCGC-3'; SEQ ID NO: 1), p53 antisense (5'-GACAGCATCAAATCATCC-3'; SEQ ID NO: 2), and GAPDH forward (5'- CATTGACCTCAACTACATGG-3'; SEQ ID NO: 3), anti-sense GAPDH (5'-GCCATGCCAGTGAGCTTCC-3'; SEQ ID NO: 4). The results show that DAP is not able to stabilize an mRNA carrying a premature stop codon, thus demonstrating that DAP is not an inhibitor of NMD (Figure 5). 6. The protein translucent by DAP is functional In order to demonstrate that the protein translucent in the presence of DAP is functional, the expression of two target genes of the p53 transcription factor, p21 and Noxa, was measured in Calu-6 cells. The observed increase in their expression indicates that the synthesized p53 protein is capable of activating the target genes and is therefore functional. As previously described, Calu-6 cells were cultured in the presence of DAP (6.25 pM or 25 pM), G418 (600 pM), or DMSO as a negative control for 20 hours. RNAs were purified with RNazol (MRC) and subjected to RT-PCR as described in Gonzalez-Hilarion et al. (2012). The resulting cDNAs were then amplified after 35 PCR cycles using the p21 mRNA primers (sense: 5'-GGAAGACCATGTGGACCTGT-3'; SEQ ID NO: 5; antisense: 5'- GACAAGTGGGGAGGAGGAAG-3'; SEQ ID NO: 6); GADD45 mRNA (sense: 5'-GGAGGAGGAGGATGACATCG-3'; SEQ ID NO: 7; antisense 5'- GCTTGCAGTCAGTCTCACTC-3'; SEQ ID NO: 8); NOXA mRNA (sense: 5'-CAGAGCTGGAAGTCGAGTGT-3'; SEQ ID NO: 9; antisense 5'- AGGAGTCCCCTCATGCAAGT-3'; SEQ ID NO: 10). The results presented in Figure 6 show that even at 6.25 pM of DAP, the expression of p53 target genes increases, indicating that the p53 protein synthesized in these cells in the presence of DAP is functional. G418 also allows for functional p53 expression, but to a lesser extent than DAP. This suggests that amino acid 5, or the amino acids incorporated in the presence of G418 at the nonsense mutation site, is / are less compatible with p53 protein function than when DAP induces readthrough. 7. Test for compensatory mutations in bacteria Materials and methods 10 The bacterial strains used in this test are the Salmonella typhimurium strains TA1535, TA1537, TA98, TA100 and TA102, supplied by Moltox (Molecular Toxicology, INC, Boone, NC 28607, USA) or by culture from Collections (Public Health England, Porton Down, Salisbury SP4 OJG, UK). The test was performed in the absence or presence of a metabolic solution called mixture 15 S9 (mixture S9 of rat liver treated with aroclor. The concentration of the S9 fraction in mixture S9 is 10%). The composition of mixture S9 is given in Table 1 below. Table 1: Composition of the S9 metabolic activation solution Ingredient Final concentration Glucose-6-phosphate 5 mM NADP 4 mM KO 33 mM MgCl2 8mM Buffer Sodium phosphate PH 7.4 lOOmM Fraction S9 (Molecular Toxicology, INC, Boone, NC 28607, USA) 10% (v / v) Water to volume The final concentrations used were 0.5; 1.4; 4.1; 12.3; 37; 111.1; 333.3 and 1000 pg / well for each of the bacterial strains and in the presence or absence of mixture S9. The solvent used was dimethyl sulfoxide (DMSO), the volume of the solution containing the molecule to be tested or of DMSO alone was 25 µl per well. The positive controls used are: For tests carried out in the presence of mixture S9, 2-anthranine at 1 pg / well for strains TA98, TA100 and TA1535 or 5 pg / well for strains TA102 or TA1537. 25 For tests performed in the absence of mixture S9, various positive controls were used: 2-nitrofluorene at 0.25 pg / well for strain TA98, sodium azide at 1 pg / well for strain TA100 or at 0.5 pg / well for strain TA1535, mitomycin C at 0.25 pg / well for strain TA102 or 9-aminocridine at 25 pg / well for strain TA1537. The experiments were done once in triplicate. The treatment in the absence or presence of the S9 mixture was done by adding it 5 directly into the wells. Results The results are presented in Tables 2 and 3. No precipitate was observed in the wells when counting revertants for any dose tested, in any strain, and whether in the presence or absence of mixture S9. 10 Table 2: Primary assay without metabolic activation - direct incorporation method into the well compound strain dose (pg / well) mean revertants per well standard deviation treated / solvent ratio individual revertant per colony TA1535 2.6 DAP 1000.0 0.0 0.0 0.0 0.0 0.0 333.3 3.3 1.2 1.3 4.2.4 111.1 3.7 1.5 1.4 5.4.2 37.0 1.3 0.6 0.5 1.2.1 12.3 4.0 3.0 1.5 4.7.1 4.1 2.3 3.2 0.9 0.6.1 1.4 2.3 1.5 0.9 1.2.4 0.5 3.3 4.9 1.3 0.9.1 DMSO 2.7 1.2 2.4.2 TA1537 2.6 DAP 1000.0 0.0 0.0 0.0 0.0.0 333.3 1.3 0.6 0.5 2.1.1 111.1 3.0 3.5 1.1 1.1.7 37.0 3.3 2.9 1.3 5.0.5 12.3 2.3 2.3 0.9 5.1.1 4.1 1.3 2.3 0.5 4.0.0 1.4 1.7 0.6 0.6 2.1.2 0.5 1.3 2.3 0.5 0.0.4 DMSO 2.7 2.3 4.4.0 TA98 2.6 DAP 1000.0 3.0 2.6 0.4 2.6.1 333.3 7.3 4.2 0.9 6.4.12 111.1 6.0 4.6 0.8 5.2.11 37.0 5.3 2.9 0.7 7.7.2 12.3 8.3 2.9 1.0 5.10.10 4.1 9.3 2.1 1.2 11.7.10 1.4 11.0 1.7 1.4 12.12.9 0.5 10.7 0.6 1.3 11.10.11 DMSO 8.0 3.5 12.6.6 TA100 2.6 DAP 1000.0 0.0 0.0 0.0 0.0.0 333.3 28.3 16.2 0.7 19.19.47 111.1 36.3 8.1 0.9 42.27.40 37.0 43.7 6.8 1.0 46.36.49 12.3 40.7 5.5 1.0 47.38.37 4.1 42.0 8.7 1.0 32.47.47 1.4 44.3 4.0 1.1 42.4942 0.5 42.0 5.6 1.0 48.41.37 , DMSO 42.0 7.9 48.33.45 TA102 2.6 DAP 1000.0 3.3 3.2 0.1 2.7.1 333.3 50.0 4.6 1.5 51.45.54 111.1 54.3 16.3 1.6 47.43.73 37.0 42.3 6.0 1.2 36.43.48 12.3 35.0 2.0 1.0 33.37.35 4.1 37.0 2.6 1.1 36.35.40 1.4 34.3 5.9 1.0 41.30.32 0.5 32.0 5.6 0.9 37,26,33 DMSO 34.3 3.2 33.32.38 TA1535 NaN3 0.5 206.7 10.3 77.5 218,198,204 TA1537 9AA 25.0 553.7 65.2 207.6 583,599,479 TA98 2NF 0.25 63.7 4.5 8.0 64.59.68 TA100 NaN3 1.0 232.3 20.7 5.5 210,236,251 T Al 02 MMC 0.25 243.3 11.7 7.1 241,233,256 Abbreviations for positive tests: NaN3 sodium azide 9AA 9-Aminoacrinidine 2NF 2-nitrofluorene MMC Mitomycin C Table 3: Main assay with metabolic activation - direct incorporation method into 5 wells compound strain dose (pg / well) mean revertants per well standard deviation treated / solvent ratio individual revertant per colony TA1535 2.6 DAP 1000.0 0.0 0.0 0.0 0.0 0.0 333.3 14.7 5.0 4.4 14.10.20 111.1 13.3 2.1 4.0 11.14.15 37.0 8.3 2.1 2.5 10.9.6 12.3 4.0 2.0 1.2 6.4.2 4.1 3.3 2.9 1.0 5.5.0 1.4 2.0 2.0 0.6 4.2.0 0.5 3.0 1.7 0.9 4.4.1 DMSO 3.3 2.1 1.4.5 TA1537 2.6 DAP 1000.0 0.0 0.0 0.0 0.0.0 333.3 0.7 0.6 0.3 1.1.0 111.1 4.0 0.0 1.5 4.4.4 37.0 3.7 1.5 1.4 5.2.4 12.3 4.0 2.0 1.5 6.4.2 4.1 2.0 0.0 0.8 2.2.2 1.4 1.7 0.6 0.6 2.1.2 0.5 1.3 0.6 0.5 1.2.1 DMSO 2.7 1.2 2.2.4 TA98 2.6 DAP 1000.0 6.3 2.5 0.9 6.9.4 333.3 10.0 1.0 1.4 9.11.10 111.1 13.0 2.6 1,9 10,14,15 37.0 9.3 0.6 1.3 9.10.9 12.3 9.3 4.0 1.3 7.7.14 4.1 7.7 3.2 1.1 10.4.9 1.4 6.7 4.9 1.0 10.1.9 0.5 12.3 5.5 1.8 15.6.16 DMSO 7.0 5.0 7.12.2 T Al 00 2.6 DAP 1000.0 0.0 0.0 0.0 0.0.0 333.3 53.7 6.7 1.3 57.46.38 111.1 51.3 14.7 1.3 68.46.40 37.0 49.0 4.4 1,2 47,46,54 12,3 53,7 8,0 1,3 53,46,62 4,1 49,0 3,5 1,2 53,47,47 1,4 41,0 11,5 1,0 54,32,37 0,5 43,3 7,6 1,1 40.52.38 DMSO 40.0 18.2 28.31.61 TA102 2.6 DAP 1000.0 18.0 3.5 0.4 20.20.14 333.3 69.3 8.5 1.5 78.61.69 111.1 44.0 10.6 1.0 56,36,40 37,0 48.3 3.1 1.1 49.45.51 12.3 47.3 4.5 1.1 52.43.47 4.1 41.3 10.1 0.9 53.36.35 1.4 41.7 3.5 0.9 45.38.42 0.5 42.0 13.1 0.9 36.33.57 DMSO 45.0 8.7 51.35.49 TA1535 2 AM 1.0 137.7 11.7 41.3 148.125.140 TA1537 2AM 5.0 36.0 5.3 13.5 40.38.30 TA98 2AM 1.00 6867 69.7 98.1 767,642,651 TA100 2 AM 1.0 696.0 19.2 17.4 705,674,709 TA102 2AM 5.00 91.0 3.6 2.0 95.88.90 , Abbreviations for positive tests: 2AM: 2-Anthramin High toxicity (revealed by a decrease in revertants) is observed in the presence and absence of mixture S9 only at a dose of 1000 gg / well for all strains except strain TA98, which only shows toxicity to the molecule in the presence of mixture S9. Furthermore, strain TA1537 shows toxicity to the molecule at a concentration of 333.3 pg / well (approximately 90 mM) and only in the presence of mixture S9. Regarding the genotoxic effects of DAP, increases in the number of revertants were observed only in strain TA1535 and only in the presence of mixture S9. These increases exceeded the threshold for a positive response in this strain (i.e., with a ratio reaching 4.4), were observed at concentrations of 111.1 and 333.3 pg / well, and followed a dose-response relationship. Furthermore, the mean and most individual values ​​obtained for the number of revertants at doses ranging from 37 to 333.3 pg / well were higher than the values ​​obtained with DMSO alone. These results lead to the conclusion that DAP has a genotoxic effect in strain TA1535. No other significant increases in revertants were observed for the other strains in this study. It should be noted that a significant increase in the number of revertants was observed with the positive controls in the presence and absence of the S9 mixture compared to DMSO alone, validating the experimental conditions of the study. In conclusion, under the experimental conditions of this study, 2,6-DAP exhibits mutagenic activity only on the TA 1535 strain in the presence of a rat liver metabolic solution. 8. In vitro assay of micronuclei in murine L5178Y TK^' lymphoma cells Materials and methods The cells used were L5178Y TK+A cells obtained via ATCC (American Type Culture Collection, Manassas, USA) through Biovalley (Marne-la-Vallée, France) for micronucleus induction. The test was performed in the absence or presence of the S9 metabolic mixture, in which the S9 fraction (Moltox; Molecular Toxicology, INC, Boone, NC 28607, USA) represents 2% of the culture medium. The composition of the S9 mixture is given in Table 4 below. Table 4: Composition of mixture S9 Ingredient Volume(s) Glucose-6-phosphate (180mg / mL) 1 NADP (25mg / mL) 1 KCl (150mM) 1 Fraction S 9 (final concentration in S9mix 40% (v / v)) 2 In the test with metabolic activation, the culture medium is supplemented with 5% of S9 mixture, so the final concentration of S9 in the treated medium is 2%. The DAP concentrations tested were 0.01, 0.02, 0.04, 0.07, 0.15, 0.29, 0.58, 1.17, 2.33, and 4.66 mM. The maximum concentration was determined by the solubility of 2,6-DAP in DMSO and the experimental constraints on the applicable volume of the solution to be tested in the culture medium. Under all experimental conditions, the DMSO used as the solvent for 2,6-DAP represented only 1% (v / v) of the culture medium. The concentrations retained as not exhibiting cytotoxicity of 2,6-DAP, for genotoxic analyses are 0.02, 0.04 and 0.07 mM in the absence of mixture S9, and 0.04, 0.29 and 0.58 mM in the presence of mixture S9. The cells were treated for 24 hours in the absence of the S9 mixture, or treated for 3 hours followed by 24 hours of untreated culture when the S9 mixture was present in the culture medium. The positive controls used are mitomycin C at a final concentration of 1 pg / ml in the absence of S9 mixture or cyclophosphamide at a final concentration of 6 pg / ml in the presence of S9 mixture. The experiment was performed once, and 1000 mononuclear cells were analyzed by culture. Three doses of 2,6-DAP, DMSO alone, or positive controls in the presence and absence of the S9 mixture were analyzed. Cytotoxicity was assessed by measuring the doubling of the cell population at the end of the experiment. Results The results are shown in Table 5 below. Table 5: Results obtained with and without the S 9 mix Treatment Conditions Doses (nM) DP (% of control substance) Number of cells analyzed per culture Standard deviation Treated / solvent ratio 0 100 1000 1 a) Test without S 9 mix 0.01 91 0.02 121 1000 2 2.0 0.04 78 1000 3 3.0 0.07 97 1000 1 1.0 0.15 21 0.29 # 0.58 # 1.17 # 2.33 # 4.66 # MMC (pg / mL) 1000 100 100.0 *** 0 100 1000 1 Test with S 9 mix 0.01 76 0.02 89 0.04 91 1000 0 0.0 0.07 74 0.15 76 0.29 73 1000 1 1.0 0.58 54 1000 0 0.5 1.17 35 2.33 ............................................................... 44 4.66 40 CPA (6 pg / mL) 1000 60 60.0 *** 0: control (DMSO); MMC: Mitocynthia C; CPA: Cyclophosphamide; DP: doubling population; Statistics: 2*2 contingency table; ***: p < 0.001; #: cell concentration at the end of treatment is lower than at the beginning of treatment; a): raw data obtained with the control is equal to 0, but it has been modified to 1 to allow calculation of ratios. 2,6-DAP exhibits severe cytotoxicity at doses above 0.15 mM in the absence of the S9 mixture, with population doubling reduced by 79% to 100%. In the presence of the S9 mixture, mild cytotoxicity appears at doses above 0.07 mM, with population doubling reduced by 24% to 64.6%. No significant increase in the frequency of cells containing micronuclei was observed compared to DMSO alone, in the presence or absence of The S9 mixture indicated no genotoxic effect of 2,6-DAP. It is noteworthy that the frequency of cells with micronuclei increases significantly in the presence of positive controls, both with and without the S9 mixture, thus validating the experimental conditions of the test. In conclusion, under the experimental conditions of the study, 2,6-DAP did not induce any chromosomal damage or damage to the cellular machinery involved in cell division in mammalian L5178Y TK+ / - somatic cells in the absence or presence of rat metabolic solution. REFERENCES Baharin, MF, et al., 2015, Malaysian J Pathol. 37, 153-158. Benhabiles, H., et al., 2016, Nonsense mutation correction in human diseases: an approach for targeted medicine, Elsevier edn (Publisher: Catherine Van Der Laan). Bidou, L., et al., 2004, Gene Ther. 11, 619-627. Bidou, L., et al., 2012, Trends Mol Med. 18, 679-88. Bladen, CL, et al., 2015, Human Mutation. 36,395-402. Burchenal, JH, étal., 1949, Cancer. 2,119. Cangül, H., et al., 2015, J Clin Res Pediatr Endocrinol. 7, 323-328. Carmosino, M., et al., 2016, J. Cell. Mol. Med. doi: 10.1111 / jcmm.12926. Csânyi, B., et al., 2016, Canadian Journal of Cardiology. 1-8. Dranchak, P.K., et al., 2011, J Cell Biochem. 112,1250-1258. Du, L., et al., 2009, J Exp Med. 206, 2285-2297. Fitzhugh, M., and Writer, S., 2016, Bioworld. 27, 3-5. Friend, C., 1951, Proc Soc Exp Biol Med. 75,150-153. Gonzalez-Hilarion, S., et al., 2012, Orphanet J Rare Dis. 7, 58, Hermann, T., 2007, Cell Mol Life Sci. 64, 1841-1852. Hug, N., et al., 2016, Nucleic Acids Res. 44, 1483-1495. Jia, J., étal., 2015, Cell Death Differ. 22, 1754-1763. Keeling, K.M., Du, M., and Bedwell, D.M., 2006. Thérapies of Nonsense-Associated Diseases. Nonsense-mediated mRNA Decay - Landes Bioscience Editor : Lynne E. Maquat, 121-136. Keeling, K.M., étal., 2001, Hum Mol Genet. 10, 291-299. Kervestin, S., et al., 2012, Nat Rev Mol Cell Biol. 13, 700-712. Kosuga, M., étal., 2016, Molecular Genetics and Metabolism. 118, 190—197. Lavin, M.F., 2013, Mol Ther. 21, 1651-1652, Lee; H.L., & Dougherty, J.P.,. 2012, Pharmacol. Ther. 136, 221-66. Lin, F.-J., et al., 2016, Experimental and Therapeutic Medicine. 11, 1249-1252. Loughran, G., et al., 2014. Nucleic Acids Res, 42, 8928-8938. 5 Mansoura, MK, étal., 1999, Hum Gene Ther. 10, 861-875. Mort, M., et al., 2008, Hum Mutât. 29, 1037-1047. Popp, M.W., and Maquat, L,E, 2014, Mol Cells. 37, 1-8. Roosing, S,, étal., 2016, Hum Genet. / 35,919-921. Sangkuhl, K., et al., 2004, Hum Mol Genet. 13, 893-903. 10 Schweingruber, C., et al., 2013, Biochim Biophys Acta. / 529:612-623. Swan, S.K., 1997, Semin Nephrol. 17, 27-33. Taanman, J.-W., et al., 2003, Human Molecular Genetics, 12:1839-1845. Welch, E.M., et al., 2007, Nature. 447, 87-91. Xia, X., et al., 2016, PLoS ONE 11, e0156981. 15 Zemrani, B., etal., 2016, Eur J Med Res. 27.19. Zhao, J., et al., 2016, European Journal of Medical Genetics. 59, 396e400.

Claims

DEMANDS 1. 2,6-Diaminopurine (DAP) for its use in the treatment of a disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon selected from inflammatory diseases due to said nonsense mutation, neurodegenerative diseases due to said nonsense mutation, autoimmune diseases due to said nonsense mutation, cardiovascular diseases due to said nonsense mutation, pulmonary diseases due to said nonsense mutation, cancers due to said nonsense mutation, amyloidosis due to said nonsense mutation, Alzheimer's disease due to said nonsense mutation, atherosclerosis due to said nonsense mutation, gigantism due to said nonsense mutation, dwarfism due to said nonsense mutation, hypothyroidism due to said nonsense mutation, hyperthyroidism due to said nonsense mutation, the cystic fibrosis due to said nonsense mutation, obesity due to said nonsense mutation,Parkinson's disease due to said nonsense mutation, Niemann-Pick disease due to said nonsense mutation, familial hypercholesterolemia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, Marfan syndrome due to said nonsense mutation, lysosomal storage diseases due to said nonsense mutation, muscular dystrophies due to said nonsense mutation, hemophilia due to said nonsense mutation, late infantile neuronal ceroid lipofuscinosis due to said nonsense mutation, beta-thalassemia due to said nonsense mutation, Ehlers-Danlos syndrome due to said nonsense mutation, Dravet syndrome due to said nonsense mutation, achromatopsia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, Usher syndrome type IC due to said mutation nonsense, the musculo-contractural type of Ehlers-Danlos syndrome due to the said nonsense mutation,Alagille syndrome due to said nonsense mutation, Alström syndrome due to said nonsense mutation, antithrombin deficiency due to said nonsense mutation, Camey complex due to said nonsense mutation, Currarinon syndrome due to said nonsense mutation, Blackfan-Diamond anemia due to said nonsense mutation, erythropoietic protoporphyria due to said nonsense mutation, Fabry disease due to said nonsense mutation, congenital factor XIII deficiency due to said nonsense mutation, Bickel-Fanconi glycogenosis due to said nonsense mutation, trimethylaminuria due to said nonsense mutation, Gaucher disease due to said nonsense mutation, Rendu- disease, Osler syndrome due to said nonsense mutation, homocystinuria due to said nonsense mutation, Joubert syndrome due to said nonsense mutation, Krabbe disease due to said nonsense mutation, L-2-HG aciduria due to said nonsense mutation, methylmalonic acidemia due to said nonsense mutation, Peters-plus syndrome due to said nonsense mutation, Townes-Brocks syndrome due to said nonsense mutation, von Willebrand disease due to said nonsense mutation, Wiskott-Aldrich syndrome due to said nonsense mutation, Kabuki syndrome due to said nonsense mutation, Dorfman-Chanarin disease due to said nonsense mutation, fish eye disease due to a partial deficiency in lecithin-cholesterol acyltransferase due to said nonsense mutation, mucopolysaccharidoses due to said nonsense mutation, coenzyme Q10 deficiency due to said nonsense mutation, Zellweger syndrome due to said nonsense mutation,colorectal cancer due to said nonsense mutation, congenital enteropathy due to enteropeptidase deficiency due to said nonsense mutation, Peutz-Jeghers syndrome due to said nonsense mutation, Jervell and Lange Nielsen syndrome due to said nonsense mutation, Lynch syndrome due to said nonsense mutation, microvillus inclusion disease due to said nonsense mutation, xanthinuria due to said nonsense mutation, acidosis due to said nonsense mutation, Alport syndrome due to said nonsense mutation, Bardet-Biedl syndrome due to said nonsense mutation, Birt-Hogg-Dubé syndrome due to said nonsense mutation, Dent disease due to said nonsense mutation, Gitelman syndrome due to said nonsense mutation, hereditary leiomyomatosis-renal cancer syndrome due to said nonsense mutation, Minkowski-Chauffard disease due to said nonsense mutation, Leber congenital amaurosis due to said nonsense mutation,Dibasic protein intolerance with lysinuria due to said nonsense mutation, nephronophthisis due to said nonsense mutation, recessive polycystic kidney disease due to said nonsense mutation, pseudohypoaldosteronism due to said nonsense mutation, renal hypoplasia and dysplasia due to said nonsense mutation, clear cell renal cell carcinoma due to said nonsense mutation, type 2 papillary renal cell carcinoma due to said nonsense mutation, Ochoa syndrome due to said nonsense mutation, von Hippel-Lindau disease due to said nonsense mutation, Wilms tumor due to said nonsense mutation, X-linked hypophosphatemic rickets due to said nonsense mutation, juvenile familial hyperuricemic nephropathy due to said nonsense mutation, tuberous sclerosis of Bourneville syndrome due to said nonsense mutation, Finnish nephrotic syndrome due to said nonsense mutation, corticosteroid-resistant idiopathic nephrotic syndrome, the syndrome of,Pierson syndrome due to said nonsense mutation, Denys-Drash syndrome due to said nonsense mutation, Schimke syndrome due to said nonsense mutation, primary glucocorticoid resistance due to said nonsense mutation, hypophosphatemic vitamin D-resistant rickets due to said nonsense mutation, primary hyperoxaluria type 1 due to said nonsense mutation, pseudohypoaldosteronism type 1 (PHA1) due to said nonsense mutation, renal tubular acidosis type 2 due to said nonsense mutation, Bassen-Komzweig disease due to said nonsense mutation, Alpers-Huttenlocher syndrome due to said nonsense mutation, carbamoyl phosphate synthase I (CPS1) deficiency due to said nonsense mutation, cholesterol ester storage disease due to said nonsense mutation, citrine deficiency due to said mutation nonsense, Dubin-Johnson syndrome due to said nonsense mutation, factor V deficiency due to said nonsense mutation,glycogen storage disease due to said nonsense mutation, hemophilia due to factor VIII or IX deficiency due to said nonsense mutation, hepatocellular carcinoma due to said nonsense mutation, hepatoeythropoietic porphyria due to said nonsense mutation, familial spastic paraplegia due to said nonsense mutation, rho-betalipoproteinemia due to said nonsense mutation, constitutional factor XI deficiency due to said nonsense mutation, adult-onset diabetes mellitus due to said nonsense mutation, microcytic hypochromic anemia due to said nonsense mutation, mitochondrial DNA depletion syndrome due to said nonsense mutation, phenylketonuria due to said nonsense mutation, polycystic liver disease due to said nonsense mutation, porphyria cutanea tarda due to said nonsense mutation, familial progressive intrahepatic cholestasis due to said nonsense mutation, Wilson's disease due to said nonsense mutation,autosomal dominant hypercholesterolemia due to said nonsense mutation, factor XII deficiency due to said nonsense mutation, factor X deficiency due to said nonsense mutation, hypofibrinogenemia due to said nonsense mutation, afibrinogenemia due to said nonsense mutation, factor VII deficiency due to said nonsense mutation, agammaglobulinemia due to said nonsense mutation, amegakaryocytic thrombocytopenia due to said nonsense mutation, congenital dyserythropoietic anemia type 2 due to said nonsense mutation, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) due to said nonsense mutation, centronuclear myopathies due to said nonsense mutation, limb-girdle muscular dystrophies due to said nonsense mutation, Miyoshi myopathy due to said mutation nonsense, Ullrich congenital muscular dystrophy due to said nonsense mutation, spinal muscular atrophy due to said nonsense mutation, dystrophic epidermolysis bullosa due to said nonsense mutation, Hailey-Hailey disease due to said nonsense mutation, Herlitz type junctional epidermolysis bullosa due to said nonsense mutation, Netherton syndrome due to said nonsense mutation, Hurler syndrome due to said nonsense mutation, LINCL (Infantile Neuronal Ceroid Lipofuscinosis) due to said nonsense mutation.

2. A pharmaceutical composition comprising at least 2,6-diaminopurine (DAP) according to claim 1 and a pharmaceutically acceptable excipient for its use in the treatment of a disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon selected from inflammatory diseases due to said nonsense mutation, neurodegenerative diseases due to said nonsense mutation, autoimmune diseases due to said nonsense mutation, cardiovascular diseases due to said nonsense mutation, pulmonary diseases due to said nonsense mutation, cancers due to said nonsense mutation, amyloidosis due to said nonsense mutation, Alzheimer's disease due to said nonsense mutation, atherosclerosis due to said nonsense mutation, gigantism due to said nonsense mutation, dwarfism due to said nonsense mutation, hypothyroidism due to said nonsense mutation, hyperthyroidism due to the aforementioned nonsense mutation,cystic fibrosis due to said nonsense mutation, obesity due to said nonsense mutation, Parkinson's disease due to said nonsense mutation, Niemann-Pick disease due to said nonsense mutation, familial hypercholesterolemia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, Marfan syndrome due to said nonsense mutation, lysosomal storage diseases due to said nonsense mutation, muscular dystrophies due to said nonsense mutation, hemophilia due to said nonsense mutation, late infantile neuronal ceroid lipofuscinosis due to said nonsense mutation, beta-thalassemia due to said nonsense mutation, Ehlers-Danlos syndrome due to said nonsense mutation, Dravet syndrome due to said nonsense mutation, achromatopsia due to said nonsense mutation, retinitis pigmentary due to said nonsense mutation, Usher syndrome type IC due to said nonsense mutation,Ehlers-Danlos syndrome (musculoskeletal type) due to said nonsense mutation, Alagille syndrome due to said nonsense mutation, Alström syndrome due to said nonsense mutation, antithrombin deficiency due to said nonsense mutation, Camey complex due to said nonsense mutation, Currarinon syndrome due to said nonsense mutation, Blackfan-Diamond anemia due to said nonsense mutation, erythropoietic protoporphyria due to said nonsense mutation, Fabry disease due to said, nonsense mutation, congenital factor XIII deficiency due to said nonsense mutation, Bickel-Fanconi glycogenosis due to said nonsense mutation, trimethylaminuria due to said nonsense mutation, Gaucher disease due to said nonsense mutation, Rendu-Osler disease due to said nonsense mutation, rhomocystinuria due to said nonsense mutation, Joubert syndrome due to said nonsense mutation, Krabbe disease due to said nonsense mutation, L-2-HG aciduria due to said nonsense mutation, methylmalonic acidemia due to said nonsense mutation, Peters-plus syndrome due to said nonsense mutation, Townes-Brocks syndrome due to said nonsense mutation, von Willebrand disease due to said nonsense mutation, Wiskott-Aldrich syndrome due to said nonsense mutation, Kabuki syndrome due to said nonsense mutation, Dorfman-Chanarin disease due to said nonsense mutation,fish eye disease due to a partial deficiency in lecithin-cholesterol acyltransferase due to said nonsense mutation, mucopolysaccharidoses due to said nonsense mutation, coenzyme Q10 deficiency due to said nonsense mutation, Zellweger syndrome due to said nonsense mutation, colorectal cancer due to said nonsense mutation, congenital enteropathy due to enteropeptidase deficiency due to said nonsense mutation, Peutz-Jeghers syndrome due to said nonsense mutation, Jervell and Lange Nielsen syndrome due to said nonsense mutation, Lynch syndrome due to said nonsense mutation, microvillus inclusion disease due to said nonsense mutation, xanthinuria due to said nonsense mutation, acidosis due to said nonsense mutation, Alport syndrome due to said mutation nonsense, Bardet-Biedl syndrome due to said mutation; nonsense, Birt-Hogg-Dubé syndrome due to said mutation; nonsense,Dent disease due to said nonsense mutation, Gitelman syndrome due to said nonsense mutation, hereditary leiomyomatosis-renal cancer syndrome due to said nonsense mutation, Minkowski-Chauffard disease due to said nonsense mutation, Leber congenital amaurosis due to said nonsense mutation, dibasic protein intolerance with lysinuria due to said nonsense mutation, nephronophthisis due to said nonsense mutation, recessive polycystic kidney disease due to said nonsense mutation, pseudohypoaldosteronism due to said nonsense mutation, renal hypoplasia and dysplasia due to said nonsense mutation, clear cell renal cell carcinoma due to said nonsense mutation, type 2 papillary renal cell carcinoma due to said nonsense mutation, Ochoa syndrome due to said nonsense mutation, von Hippel-Lindau disease due to said nonsense mutation, Wilms tumor due to said nonsense mutation,X-linked hypophosphatemic rickets due to the aforementioned nonsense mutation, the, juvenile familial hyperuricemic nephropathy due to said nonsense mutation, tuberous sclerosis due to said nonsense mutation, Finnish nephrotic syndrome due to said nonsense mutation, corticosteroid-resistant idiopathic nephrotic syndrome, Pierson syndrome due to said nonsense mutation, Denys-Drash syndrome due to said nonsense mutation, Schimke syndrome due to said nonsense mutation, primary glucocorticoid resistance due to said nonsense mutation, hypophosphatemic vitamin D-resistant rickets due to said nonsense mutation, primary hyperoxaluria type 1 due to said nonsense mutation, pseudohypoaldosteronism type 1 (PHA1) due to said nonsense mutation, renal tubular acidosis type 2 due to said nonsense mutation, Bassen-Komzweig disease due to said mutation nonsense, Alpers-Huttenlocher syndrome due to said nonsense mutation,carbamoyl phosphate synthase I (CPS1) deficiency due to said nonsense mutation, cholesterol ester storage disease due to said nonsense mutation, citrine deficiency due to said nonsense mutation, Dubin-Johnson syndrome due to said nonsense mutation, factor V deficiency due to said nonsense mutation, glycogen storage disease due to said nonsense mutation, hemophilia due to factor VIII or IX deficiency due to said nonsense mutation, hepatocellular carcinoma due to said nonsense mutation, hepatoeythropoietic porphyria due to said nonsense mutation, familial spastic paraplegia due to said nonsense mutation, rho-betalipoproteinemia due to said nonsense mutation, constitutional factor XI deficiency due to said nonsense mutation, adult-onset diabetes in young people due to said nonsense mutation, microcytic hypochromic anemia due to said nonsensical mutation,mitochondrial DNA depletion syndrome due to said nonsense mutation, phenylketonuria due to said nonsense mutation, polycystic liver disease due to said nonsense mutation, porphyria cutanea tarda due to said nonsense mutation, progressive familial intrahepatic cholestasis due to said nonsense mutation, Wilson's disease due to said nonsense mutation, autosomal dominant hypercholesterolemia due to said nonsense mutation, factor XII deficiency due to said nonsense mutation, factor X deficiency due to said nonsense mutation, hypofibrinogenemia due to said nonsense mutation, afibrinogenemia due to said nonsense mutation, factor VII deficiency due to said nonsense mutation, agammaglobulinemia due to said nonsense mutation, amegakaryocytic thrombocytopenia due to said nonsense mutation, anemia congenital dyserythropoietic type 2 due to the aforementioned nonsense mutation,Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) due to said nonsense mutation, centronuclear myopathies due to said mutation, nonsense, limb-girdle muscular dystrophies due to said nonsense mutation, Miyoshi myopathy due to said nonsense mutation, Ullrich congenital muscular dystrophy due to said nonsense mutation, spinal muscular atrophy due to said nonsense mutation, dystrophic epidermolysis bullosa due to said nonsense mutation, Hailey-Hailey disease due to said nonsense mutation, Herlitz junctional epidermolysis bullosa due to said nonsense mutation, Netherton syndrome due to said nonsense mutation, Hurler syndrome due to said nonsense mutation, LINCL (Infantile Neuronal Ceroid Lipofuscinosis) due to said nonsense mutation.

3. Combination of 2,6-diaminopurine (DAP) and a compound possessing readthrough activity for use in the treatment of a disease due to a nonsense mutation in a gene leading to the premature introduction of a UGA stop codon selected from inflammatory diseases due to said nonsense mutation, neurodegenerative diseases due to said nonsense mutation, autoimmune diseases due to said nonsense mutation, cardiovascular diseases due to said nonsense mutation, pulmonary diseases due to said nonsense mutation, cancers due to said nonsense mutation, amyloidosis due to said nonsense mutation, Alzheimer's disease due to said nonsense mutation, atherosclerosis due to said nonsense mutation, gigantism due to said nonsense mutation, dwarfism due to said nonsense mutation, hypothyroidism due to said nonsense mutation, hyperthyroidism due to said nonsense mutation, cystic fibrosis due to said nonsense mutation,obesity due to said nonsense mutation, Parkinson's disease due to said nonsense mutation, Niemann-Pick disease due to said nonsense mutation, familial hypercholesterolemia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, Marfan syndrome due to said nonsense mutation, lysosomal storage diseases due to said nonsense mutation, muscular dystrophies due to said nonsense mutation, hemophilia due to said nonsense mutation, late infantile neuronal ceroid lipofuscinosis due to said nonsense mutation, beta-thalassemia due to said nonsense mutation, Ehlers-Danlos syndrome due to said nonsense mutation, Dravet syndrome due to said nonsense mutation, achromatopsia due to said nonsense mutation, retinitis pigmentosa due to said nonsense mutation, syndrome Usher syndrome of type IC due to said nonsense mutation, Ehlers-Danlos syndrome of the musculo-contractural type due to said nonsense mutation,the syndrome, Alagille due to said nonsense mutation, Alström syndrome due to said nonsense mutation, antithrombin deficiency due to said nonsense mutation, Carney complex due to said nonsense mutation, Currarinon syndrome due to said nonsense mutation, Blackfan-Diamond anemia due to said nonsense mutation, erythropoietic protoporphyria due to said nonsense mutation, Fabry disease due to said nonsense mutation, congenital factor XIII deficiency due to said nonsense mutation, Bickel-Fanconi glycogenosis due to said nonsense mutation, trimethylaminuria due to said nonsense mutation, Gaucher disease due to said nonsense mutation, Rendu-Osler disease due to said nonsense mutation, homocystinuria due to said nonsense mutation, Joubert syndrome due to said nonsense mutation, Krabbe disease due to said nonsense mutation, L-2-HG aciduria due to said nonsense mutation,methylmalonic acidemia due to said nonsense mutation, Peters-plus syndrome due to said nonsense mutation, Townes-Brocks syndrome due to said nonsense mutation, von Willebrand disease due to said nonsense mutation, Wiskott-Aldrich syndrome due to said nonsense mutation, Kabuki syndrome due to said nonsense mutation, Dorfman-Chanarin disease due to said nonsense mutation, fish eye disease due to a partial deficiency of lecithin-cholesterol acyltransferase due to said nonsense mutation, mucopolysaccharidoses due to said nonsense mutation, coenzyme Q10 deficiency due to said nonsense mutation, Zellweger syndrome due to said nonsense mutation, colorectal cancer due to said nonsense mutation, congenital enteropathy due to enteropeptidase deficiency due to said nonsense mutation, Peutz-Jeghers syndrome due to said nonsense mutation, Jervell and Lange Nielsen syndrome due to said nonsense mutation,Lynch syndrome due to said nonsense mutation, microvillus inclusion disease due to said nonsense mutation, xanthinuria due to said nonsense mutation, acidosis due to said nonsense mutation, Alport syndrome due to said nonsense mutation, Bardet-Biedl syndrome due to said nonsense mutation, Birt-Hogg-Dubé syndrome due to said nonsense mutation, Dent disease due to said nonsense mutation, Gitelman syndrome due to said nonsense mutation, hereditary leiomyomatosis-renal cancer syndrome due to said nonsense mutation, Minkowski-Chauffard disease due to said nonsense mutation, Leber congenital amaurosis due to said nonsense mutation, dibasic protein intolerance with lysinuria due to said nonsense mutation, nephronophthisis due to said nonsense mutation, recessive polycystic kidney disease due to said nonsense mutation, pseudohypoaldosteronism due to said nonsense mutation,renal hypoplasia and dysplasia due to, to the said nonsense mutation, clear cell renal cell carcinoma due to the said nonsense mutation, papillary renal cell carcinoma type 2 due to the said nonsense mutation, Ochoa syndrome due to the said nonsense mutation, von Hippel-Lindau disease due to the said nonsense mutation, Wilms tumor due to the said nonsense mutation, X-linked hypophosphatemic rickets due to the said nonsense mutation, juvenile familial hyperuricemic nephropathy due to the said nonsense mutation, tuberous sclerosis due to the said nonsense mutation, Finnish nephrotic syndrome due to the said nonsense mutation, corticosteroid-resistant idiopathic nephrotic syndrome, Pierson syndrome due to the said nonsense mutation, Denys-Drash syndrome due to the said nonsense mutation, Schimke syndrome due to the said mutation nonsense, resistance to the primary glucocorticoid due to said nonsense mutation,Vitamin D-resistant hypophosphatemic rickets due to said nonsense mutation, primary hyperoxaluria type 1 due to said nonsense mutation, pseudohypoaldosteronism type 1 (PHA1) due to said nonsense mutation, renal tubular acidosis type 2 due to said nonsense mutation, Bassen-Kornzweig disease due to said nonsense mutation, Alpers-Huttenlocher syndrome due to said nonsense mutation, carbamoyl phosphate synthase I (CPS1) deficiency due to said nonsense mutation, cholesterol ester storage disease due to said nonsense mutation, citrine deficiency due to said nonsense mutation, Dubin-Johnson syndrome due to said nonsense mutation, factor V deficiency due to said nonsense mutation, glycogen storage disease due to said nonsense mutation, hemophilia due to factor VIII or IX deficiency due to said nonsense mutation, hepatocellular carcinoma due to said nonsense mutation,hepatoeythropoietic porphyria due to said nonsense mutation, familial spastic paraplegia due to said nonsense mutation, hypo-betalipoproteinemia due to said nonsense mutation, constitutional factor XI deficiency due to said nonsense mutation, adult-onset diabetes in young people due to said nonsense mutation, microcytic hypochromic anemia due to said nonsense mutation, mitochondrial DNA depletion syndrome due to said nonsense mutation, phenylketonuria due to said nonsense mutation, polycystic liver disease due to said nonsense mutation, porphyria cutanea tarda due to said nonsense mutation, familial progressive intrahepatic cholestasis due to said nonsense mutation, Wilson's disease due to said nonsense mutation, autosomal dominant hypercholesterolemia due to said nonsense mutation, factor XII deficiency due to said mutation nonsense, factor X deficiency due to said nonsense mutation,hypofibrinogenemia due to said nonsense mutation, afibrinogenemia due to said nonsense mutation, factor VII deficiency, due to said nonsense mutation, agammaglobulinemia due to said nonsense mutation, amegakaryocytic thrombocytopenia due to said nonsense mutation, congenital dyserythropoietic anemia type 2 due to said nonsense mutation, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) due to said nonsense mutation, centronuclear myopathies due to said nonsense mutation, limb-girdle muscular dystrophies due to said nonsense mutation, Miyoshi myopathy due to said nonsense mutation, Ullrich congenital muscular dystrophy due to said nonsense mutation, spinal muscular atrophy due to said nonsense mutation, dystrophic epidermolysis bullosa due to said nonsense mutation, Hailey-Hailey disease due to said nonsense mutation, junctional epidermolysis bullosa type Herlitz syndrome due to said nonsense mutation, Netherton syndrome due to said nonsense mutation, Hurler syndrome due to said nonsense mutation,LINCL (Late Infantile Neuronal Ceroid Lipofuscinosis) due to said nonsense mutation, characterized in that said compound possessing readthrough activity is selected from the group consisting of 6-amino-5-nitro-4-(aD-ribofuranosylamino)-pyrimidine, 6-amino-5-nitro-4-(PD-ribofuranosylamino)-pyrimidine, ataluren, gentamicin, geneticin, paromomycin and paromomycin derivatives such as NB30; NB54; NB74; NB84, amikacin, tobramycin, pyramicin and pyramycin derivatives such as TC001; TC003; TC007; TC032, kanamycin and kanamycin derivatives such as JL022; JL023, amlexanox, RTC 13 (Lavin, 2013), RTC 14 (Lavin, 2013), 3-(2-4E(l,l dimethyl propyl)-phenoxy-acetylamino)-benzoic acid, 3-(2-(4-isopropyl-3-methyl-phenoxy)-acetylamino)-benzoic acid, negamycin, tylosin, josamycin, spiramycin, and 3-(2-(4-tert-butyl-phenoxy)-acetylamino)-benzoic acid.

4. Pharmaceutical composition for use according to claim 2, characterized in that it further comprises a compound having readthrough activity selected from the group consisting of 6-amino-5-nitro-4-(aD-ribofuranosylamino)-pyrimidine, 6-amino-5-nitro-4-(PD-ribofuranosylamino)-pyrimidine, ataluren, gentamicin, geneticin, paromomycin and paromomycin derivatives such as NB30; NB54; NB74; NB84, amikacin, tobramycin, pyramicin and pyramycin derivatives such as TC001; TC003; TC007; TC032, kanamycin and kanamycin derivatives such as JL022; JL023, amlexanox, RTC 13 (Lavin, 2013), RTC 14 (Lavin, 2013), 3-(2-4E(l,l dimethyl propyl)-phenoxy-acetylamino)-benzoic acid, 3-(2-(4-isopropyl-3-methyl-phenoxy)-acetylamino)-benzoic acid, negamycin, tylosin, josamycin, spiramycin, and 3-(2-(4-tert-butyl-phenoxy)-acetylamino)-benzoic acid.

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