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European journal of medicinal chemistry
Aug 15, 2020;200 112436.

Pharmacological approaches for targeting cystic fibrosis nonsense mutations.

Jyoti Sharma, Kim M Keeling, Steven M Rowe
Author Information
  1. Jyoti Sharma: Department of Medicine, University of Alabama at Birmingham (UAB), USA; Department of Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), USA.
  2. Kim M Keeling: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham (UAB), USA; Department of Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), USA.
  3. Steven M Rowe: Department of Medicine, University of Alabama at Birmingham (UAB), USA; Department of Pediatrics, University of Alabama at Birmingham (UAB), USA; Department of Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham (UAB), USA. Electronic address: smrowe@uab.edu.
PMID: 32512483 DOI: 10.1016/j.ejmech.2020.112436

Abstract

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.

Keywords

CFTR Combination therapy Nonsense mutations Translational readthrough

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Grants

  1. P30 DK072482/NIDDK NIH HHS
  2. R35 HL135816/NHLBI NIH HHS

MeSH Term

Aminophenols
Aminopyridines
Animals
Benzodioxoles
Codon, Nonsense
Cystic Fibrosis
Dose-Response Relationship, Drug
Humans
Indoles
Molecular Structure
Mutation
Pyrazoles
Pyridines
Pyrrolidines
Quinolones
Structure-Activity Relationship

Chemicals

Aminophenols
Aminopyridines
Benzodioxoles
Codon, Nonsense
Indoles
Pyrazoles
Pyridines
Pyrrolidines
Quinolones
tezacaftor
ivacaftor
lumacaftor
elexacaftor
Journal Article Review
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Word Cloud

Created with Highcharts 10.0.0mutationsCFfibrosisCFTRreadthroughapproachestherapiesnonsensecysticdefectscombinationtranslationalefficacysuppressionlimitationsNMDtherapyCysticmonogenicautosomalrecessivedisorderclinicalmanifestationsdiseasecaused∼2000transmembraneconductanceregulatorproteinunlikelyoneapproachwillefficientcorrectingrecentapprovalsivacaftorlumacaftor/ivacaftorelexacaftor/tezacaftor/ivacaftorrepresentgenesisneweraprecisionmedicinepatientpopulationreviewdiscusstargetedmonoexaminecurrentstatusreadthrough/nonsenseincludingnon-nativeaminoacidincorporationPTCsnonsense-mediatedmRNAdecayalongtackleelaboratecombiningvariousagentsinhibitorscorrector/potentiatorsimprovesafetymutationspecificstrategiesdirectedtowardsbasicpositivelyimpactpatientsbearingPharmacologicaltargetingCombinationNonsenseTranslational

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