Readthrough Activators and Nonsense-Mediated MRNA Decay Inhibitor Molecules: Real Potential in Many Genetic Diseases Harboring Premature Termination Codons

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2024 Mar 28

PMID 38543100

Authors

Nesrine Benslimane

Camille Loret

Pauline Chazelas

Frederic Favreau

Pierre-Antoine Faye

Fabrice Lejeune

Anne-Sophie Lia

Affiliations

Soon will be listed here.

Abstract

Nonsense mutations that generate a premature termination codon (PTC) can induce both the accelerated degradation of mutated mRNA compared with the wild type version of the mRNA or the production of a truncated protein. One of the considered therapeutic strategies to bypass PTCs is their "readthrough" based on small-molecule drugs. These molecules promote the incorporation of a near-cognate tRNA at the PTC position through the native polypeptide chain. In this review, we detailed the various existing strategies organized according to pharmacological molecule types through their different mechanisms. The positive results that followed readthrough molecule testing in multiple neuromuscular disorder models indicate the potential of this approach in peripheral neuropathies.

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References

Guglieri M, Bushby K . Molecular treatments in Duchenne muscular dystrophy. Curr Opin Pharmacol. 2010; 10(3):331-7. DOI: 10.1016/j.coph.2010.03.005. View

Borovinskaya M, Pai R, Zhang W, Schuwirth B, Holton J, Hirokawa G . Structural basis for aminoglycoside inhibition of bacterial ribosome recycling. Nat Struct Mol Biol. 2007; 14(8):727-32. DOI: 10.1038/nsmb1271. View

Guthrie O . Aminoglycoside induced ototoxicity. Toxicology. 2008; 249(2-3):91-6. DOI: 10.1016/j.tox.2008.04.015. View

Lynch S, Gonzalez R, Puglisi J . Comparison of X-ray crystal structure of the 30S subunit-antibiotic complex with NMR structure of decoding site oligonucleotide-paromomycin complex. Structure. 2003; 11(1):43-53. DOI: 10.1016/s0969-2126(02)00934-6. View

Li G, Rice C . The signal for translational readthrough of a UGA codon in Sindbis virus RNA involves a single cytidine residue immediately downstream of the termination codon. J Virol. 1993; 67(8):5062-7. PMC: 237898. DOI: 10.1128/JVI.67.8.5062-5067.1993. View

Du L, Jung M, Damoiseaux R, Completo G, Fike F, Ku J . A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Mol Ther. 2013; 21(9):1653-60. PMC: 3776636. DOI: 10.1038/mt.2013.150. View

Poole E, Brown C, Tate W . The identity of the base following the stop codon determines the efficiency of in vivo translational termination in Escherichia coli. EMBO J. 1995; 14(1):151-8. PMC: 398062. DOI: 10.1002/j.1460-2075.1995.tb06985.x. View

Sabbavarapu N, Shavit M, Degani Y, Smolkin B, Belakhov V, Baasov T . Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations. ACS Med Chem Lett. 2016; 7(4):418-23. PMC: 4834649. DOI: 10.1021/acsmedchemlett.6b00006. View

Singh G, Rebbapragada I, Lykke-Andersen J . A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay. PLoS Biol. 2008; 6(4):e111. PMC: 2689706. DOI: 10.1371/journal.pbio.0060111. View

10.

Gonzalez-Hilarion S, Beghyn T, Jia J, Debreuck N, Berte G, Mamchaoui K . Rescue of nonsense mutations by amlexanox in human cells. Orphanet J Rare Dis. 2012; 7:58. PMC: 3562214. DOI: 10.1186/1750-1172-7-58. View

11.

Dunant P, Walter M, Karpati G, Lochmuller H . Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscle. Muscle Nerve. 2003; 27(5):624-7. DOI: 10.1002/mus.10341. View

12.

Clancy J, Bebok Z, Ruiz F, King C, Jones J, Walker L . Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med. 2001; 163(7):1683-92. DOI: 10.1164/ajrccm.163.7.2004001. View

13.

DiVincenzo C, Elzinga C, Medeiros A, Karbassi I, Jones J, Evans M . The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2015; 2(6):522-9. PMC: 4303222. DOI: 10.1002/mgg3.106. View

14.

Du M, Jones J, Lanier J, Keeling K, Lindsey J, Tousson A . Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J Mol Med (Berl). 2002; 80(9):595-604. DOI: 10.1007/s00109-002-0363-1. View

15.

Bidou L, Bugaud O, Belakhov V, Baasov T, Namy O . Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells. RNA Biol. 2017; 14(3):378-388. PMC: 5367250. DOI: 10.1080/15476286.2017.1285480. View

16.

Sharma J, Du M, Wong E, Mutyam V, Li Y, Chen J . A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nat Commun. 2021; 12(1):4358. PMC: 8285393. DOI: 10.1038/s41467-021-24575-x. View

17.

Sylvain V, Lafarge S, Bignon Y . Dominant-negative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line. Int J Oncol. 2002; 20(4):845-53. View

18.

Beier H, Barciszewska M, Krupp G, Mitnacht R, Gross H . UAG readthrough during TMV RNA translation: isolation and sequence of two tRNAs with suppressor activity from tobacco plants. EMBO J. 1984; 3(2):351-6. PMC: 557348. DOI: 10.1002/j.1460-2075.1984.tb01810.x. View

19.

Lynch M, Kewalramani A . Messenger RNA surveillance and the evolutionary proliferation of introns. Mol Biol Evol. 2003; 20(4):563-71. DOI: 10.1093/molbev/msg068. View

20.

Trzaska C, Amand S, Bailly C, Leroy C, Marchand V, Duvernois-Berthet E . 2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations. Nat Commun. 2020; 11(1):1509. PMC: 7083880. DOI: 10.1038/s41467-020-15140-z. View