Current development of CFTR potentiators in the last decade

Spanò, Virginia; Venturini, Arianna; Genovese, Michele; Barreca, Marilia; Raimondi, Maria Valeria; Montalbano, Alessandra; Galietta, Luis J V; Barraja, Paola

doi:10.1016/j.ejmech.2020.112631

Cited by 21 publications

(12 citation statements)

References 48 publications

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“…In the last decade, several drugs able to restore defective mutant CFTR activity have been approved for the treatment of CF patients [ 3 , 5 ]. In this respect, molecules that improve CFTR activity by increasing its open channel probability are called “potentiators”, whereas molecules that improve the proper folding and stability of the mutant protein, increasing its trafficking to the plasma membrane, are called “correctors” [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Capurro

Tomati

Sondo

et al. 2021

IJMS

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Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.

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Section: Introductionmentioning

confidence: 99%

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Capurro

Tomati

Sondo

et al. 2021

IJMS

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“…Today, there is a new generation of drugs available known as CFTR modulator drugs [72,73], which are small molecules which enhance CFTR or restore the decreased levels of proteins on the cell surface. These drugs were initially synthesized to correct the CFTR genetic defects that occurred in CF.…”

Section: Cftr Modulatorsmentioning

confidence: 99%

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

et al. 2021

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In recent years, numerous pathways were explored in the pathogenesis of COPD in the quest for new potential therapeutic targets for more personalised medical care. In this context, the study of the cystic fibrosis transmembrane conductance regulator (CFTR) began to gain importance, especially since the advent of the new CFTR modulators which had the potential to correct this protein’s dysfunction in COPD. The CFTR is an ion transporter that regulates the hydration and viscosity of mucous secretions in the airway. Therefore, its abnormal function favours the accumulation of thicker and more viscous secretions, reduces the periciliary layer and mucociliary clearance, and produces inflammation in the airway, as a consequence of a bronchial infection by both bacteria and viruses. Identifying CFTR dysfunction in the context of COPD pathogenesis is key to fully understanding its role in the complex pathophysiology of COPD and the potential of the different therapeutic approaches proposed to overcome this dysfunction. In particular, the potential of the rehydration of mucus and the role of antioxidants and phosphodiesterase inhibitors should be discussed. Additionally, the modulatory drugs which enhance or restore decreased levels of the protein CFTR were recently described. In particular, two CFTR potentiators, ivacaftor and icenticaftor, were explored in COPD. The present review updated the pathophysiology of the complex role of CFTR in COPD and the therapeutic options which could be explored.

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“…Cancer has been the second leading cause of mortality worldwide, causing approximately 10 million deaths in 2020 [ 6 ]. In the past decades, substantial efforts have been made to unveil the pathogenesis of cancers and new anticancer drugs have been developed [ 7 , 8 , 9 , 10 ]. Here, we review the original resources, anticancer effects, mechanisms, and clinical applications of selected marine-derived compounds including cytarabine (the first approved marine-derived anticancer drug), eribulin (a microtubule-depolymerizing drug), marizomib (a proteasome inhibitor), plitidepsin (a DNA synthesis inhibitor), trabectedin (a nucleotide drug), adcetris (an antibody drug conjugate), zalypsis (a new DNA binding alkaloid), and the largazole analogue OKI-179 (an HDAC inhibitor) ( Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms

Yao

Jiang

2021

Marine Drugs

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Worldwide, 19.3 million new cancer cases and almost 10.0 million cancer deaths occur each year. Recently, much attention has been paid to the ocean, the largest biosphere of the earth that harbors a great many different organisms and natural products, to identify novel drugs and drug candidates to fight against malignant neoplasms. The marine compounds show potent anticancer activity in vitro and in vivo, and relatively few drugs have been approved by the U.S. Food and Drug Administration for the treatment of metastatic malignant lymphoma, breast cancer, or Hodgkin′s disease. This review provides a summary of the anticancer effects and mechanisms of action of selected marine compounds, including cytarabine, eribulin, marizomib, plitidepsin, trabectedin, zalypsis, adcetris, and OKI-179. The future development of anticancer marine drugs requires innovative biochemical biology approaches and introduction of novel therapeutic targets, as well as efficient isolation and synthesis of marine-derived natural compounds and derivatives.

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Current development of CFTR potentiators in the last decade

Cited by 21 publications

References 48 publications

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms

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