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Article ; Online: Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.

Ferreira, Filipa C / Buarque, Camilla D / Lopes-Pacheco, Miquéias

2024 Volume 29, Issue 4

Abstract: The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent ... ...

Abstract	The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators-small molecules acting on the basic molecular defect in CF-have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA's) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.
MeSH term(s)	Humans ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Quality of Life ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Benzodioxoles/pharmacology ; Benzodioxoles/therapeutic use ; Aminophenols/pharmacology ; Aminophenols/therapeutic use ; Mutation ; Chemistry Techniques, Synthetic ; Aminopyridines ; Indoles ; Pyrazoles ; Pyridines ; Pyrrolidines ; Quinolones
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; elexacaftor (RRN67GMB0V) ; tezacaftor ; ivacaftor (1Y740ILL1Z) ; lumacaftor (EGP8L81APK) ; Benzodioxoles ; Aminophenols ; CFTR protein, human ; Aminopyridines ; Indoles ; Pyrazoles ; Pyridines ; Pyrrolidines ; Quinolones
Language	English
Publishing date	2024-02-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules29040821
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Article ; Online: PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR.

Ferreira, Filipa C / Amaral, Margarida D / Bacalhau, Mafalda / Lopes-Pacheco, Miquéias

European journal of pharmacology

2024 Volume 967, Page(s) 176390

Abstract: The deletion of a phenylalanine at position 508 (p.Phe508del) in the CFTR anion channel is the most prevalent variant in people with Cystic Fibrosis (CF). This variant impairs folding and stability of the CF transmembrane conductance regulator (CFTR) ... ...

Abstract	The deletion of a phenylalanine at position 508 (p.Phe508del) in the CFTR anion channel is the most prevalent variant in people with Cystic Fibrosis (CF). This variant impairs folding and stability of the CF transmembrane conductance regulator (CFTR) protein, resulting in its defective trafficking and premature degradation. Over the last years, therapeutic accomplishments have been attained in developing small molecules that partially correct p.Phe508del-CFTR defects; however, the mechanism of action (MoA) of these compounds has only started to be uncovered. In this study, we employed biochemical, fluorescence microscopy, and functional assays to examine the efficacy and properties of PTI-801, a newly developed p.Phe508del-CFTR corrector. To exploit its MoA, we assessed PTI-801 effects in combination with low temperature, genetic revertants of p.Phe508del-CFTR (the in cis p.Val510Asp, p.Gly550Glu, p.Arg1070Trp, and 4RK) and other correctors. Our results demonstrated that PTI-801 rescues p.Phe508del-CFTR processing, PM trafficking, and channel function (upon agonist stimulation) with greater correction effects in combination with ABBV-2222, FDL-169, VX-661, or VX-809, but not with VX-445. Although PTI-801 exhibited no potentiator activity on low temperature- and corrector-rescued p.Phe508del-CFTR, this compound displayed similar behavior to that of VX-445 on genetic revertants. Such evidence associated with the lack of additivity when PTI-801 and VX-445 were combined indicates that they share a common binding site to correct p.Phe508del-CFTR defects. Despite the high efficacy of PTI-801 in combination with ABBV-2222, FDL-169, VX-661, or VX-809, these dual corrector combinations only partially restored p.Phe508del-CFTR conformational stability, as shown by the lower half-life of the mutant protein compared to that of WT-CFTR. In summary, PTI-801 likely shares a common MoA with VX-445 in rescuing p.Phe508del-CFTR, thus being a feasible alternative for the development of novel corrector combinations with greater capacity to rescue mutant CFTR folding and stability.
MeSH term(s)	Humans ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Pyridines ; Aminopyridines/pharmacology ; Benzodioxoles/pharmacology ; Mutation ; Aminophenols/therapeutic use ; Benzoates ; Benzopyrans ; Pyrazoles ; Pyrrolidines
Chemical Substances	elexacaftor (RRN67GMB0V) ; lumacaftor (EGP8L81APK) ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; GLPG2222 ; Pyridines ; Aminopyridines ; Benzodioxoles ; Aminophenols ; CFTR protein, human ; Benzoates ; Benzopyrans ; Pyrazoles ; Pyrrolidines
Language	English
Publishing date	2024-02-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2024.176390
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Article: Additive Potentiation of R334W-CFTR Function by Novel Small Molecules.

Bacalhau, Mafalda / Ferreira, Filipa C / Silva, Iris A L / Buarque, Camilla D / Amaral, Margarida D / Lopes-Pacheco, Miquéias

Journal of personalized medicine

2023 Volume 13, Issue 1

Abstract: The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that ...

Abstract	The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose−response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity.
Language	English
Publishing date	2023-01-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662248-8
ISSN	2075-4426
ISSN	2075-4426
DOI	10.3390/jpm13010102
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Article ; Online: Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A.

Lopes-Pacheco, Miquéias / Bacalhau, Mafalda / Ramalho, Sofia S / Silva, Iris A L / Ferreira, Filipa C / Carlile, Graeme W / Thomas, David Y / Farinha, Carlos M / Hanrahan, John W / Amaral, Margarida D

Cells

2022 Volume 11, Issue 1

Abstract: Although some therapeutic progress has been achieved in developing small molecules that correct F508del-CFTR defects, the mechanism of action (MoA) of these compounds remain poorly elucidated. Here, we investigated the effects and MoA of MCG1516A, a ... ...

Abstract	Although some therapeutic progress has been achieved in developing small molecules that correct F508del-CFTR defects, the mechanism of action (MoA) of these compounds remain poorly elucidated. Here, we investigated the effects and MoA of MCG1516A, a newly developed F508del-CFTR corrector. MCG1516A effects on wild-type (WT) and F508del-CFTR were assessed by immunofluorescence microscopy, and biochemical and functional assays both in cell lines and in intestinal organoids. To shed light on the MoA of MCG1516A, we evaluated its additivity to the FDA-approved corrector VX-661, low temperature, genetic revertants of F508del-CFTR (G550E, R1070W, and 4RK), and the traffic-null variant DD/AA. Finally, we explored the ability of MCG1516A to rescue trafficking and function of other CF-causing mutations. We found that MCG1516A rescues F508del-CFTR with additive effects to VX-661. A similar behavior was observed for WT-CFTR. Under low temperature incubation, F508del-CFTR demonstrated an additivity in processing and function with VX-661, but not with MCG1516A. In contrast, both compounds promoted additional effects to low temperature to WT-CFTR. MCG1516A demonstrated additivity to genetic revertant R1070W, while VX-661 was additive to G550E and 4RK. Nevertheless, none of these compounds rescued DD/AA trafficking. Both MCG1516A and VX-661 rescued CFTR processing of L206W- and R334W-CFTR with greater effects when these compounds were combined. In summary, the absence of additivity of MCG1516A to genetic revertant G550E suggests a putative binding site for this compound on NBD1:NBD2 interface. Therefore, a combination of MCG1516A with compounds able to rescue DD/AA traffic, or mimicking the actions of revertant R1070W (e.g., VX-661), could enhance correction of F508del-CFTR defects.
MeSH term(s)	Cystic Fibrosis/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Drug Discovery/methods ; Humans ; Mutation ; Protein Folding
Chemical Substances	CFTR protein, human ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2022-01-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11010136
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Article ; Online: Identification of novel F508del-CFTR traffic correctors among triazole derivatives.

Bacalhau, Mafalda / Ferreira, Filipa C / Kmit, Arthur / Souza, Felipe R / da Silva, Verônica D / Pimentel, André S / Amaral, Margarida D / Buarque, Camilla D / Lopes-Pacheco, Miquéias

European journal of pharmacology

2022 Volume 938, Page(s) 175396

Abstract: The most prevalent cystic fibrosis (CF)-causing mutation - F508del - impairs the folding of CFTR protein, resulting in its defective trafficking and premature degradation. Small molecules termed correctors may rescue F508del-CFTR and therefore constitute ...

Abstract	The most prevalent cystic fibrosis (CF)-causing mutation - F508del - impairs the folding of CFTR protein, resulting in its defective trafficking and premature degradation. Small molecules termed correctors may rescue F508del-CFTR and therefore constitute promising pharmacotherapies acting on the fundamental cause of the disease. Here, we screened a collection of triazole compounds to identify novel F508del-CFTR correctors. The functional primary screen identified four hit compounds (LSO-18, LSO-24, LSO-28, and LSO-39), which were further validated and demonstrated to rescue F508del-CFTR processing, plasma membrane trafficking, and function. To interrogate their mechanism of action (MoA), we examined their additivity to the clinically approved drugs VX-661 and VX-445, low temperature, and genetic revertants of F508del-CFTR. Rescue of F508del-CFTR processing and function by LSO-18, LSO-24, and LSO-28, but not by LSO-39, was additive to VX-661, whereas LSO-28 and LSO-39, but not LSO-18 nor LSO-24, were additive to VX-445. All compounds under investigation demonstrated additive rescue of F508del-CFTR processing and function to low temperature as well as to rescue by genetic revertants G550E and 4RK. Nevertheless, none of these compounds was able to rescue processing nor function of DD/AA-CFTR, and LSO-39 (similarly to VX-661) exhibited no additivity to genetic revertant R1070W. From these findings, we suggest that LSO-39 (like VX-661) has a putative binding site at the NBD1:ICL4 interface, LSO-18 and LSO-24 seem to share the MoA with VX-445, and LSO-28 appears to act by a different MoA. Altogether, these findings represent an encouraging starting point to further exploit this chemical series for the development of novel CFTR correctors.
Language	English
Publishing date	2022-11-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2022.175396
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Zs.A 522: Show issues

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Article ; Online: Pathogenic fungi: an unacknowledged risk at coastal resorts? New insights on microbiological sand quality in Portugal.

Sabino, Raquel / Veríssimo, Cristina / Cunha, Maria Ana / Wergikoski, Bela / Ferreira, Filipa C / Rodrigues, Raquel / Parada, Helena / Falcão, Leonor / Rosado, Laura / Pinheiro, Catarina / Paixão, Eleonora / Brandão, João

Marine pollution bulletin

2011 Volume 62, Issue 7, Page(s) 1506–1511

Abstract: Whilst the potential impact on beach users from microorganisms in water has received considerable attention, there has been relatively little investigation into microbial contaminants in sand. Thirty three beaches across Portugal were analyzed during a ... ...

Abstract	Whilst the potential impact on beach users from microorganisms in water has received considerable attention, there has been relatively little investigation into microbial contaminants in sand. Thirty three beaches across Portugal were analyzed during a five year period (2006-2010) to determine the presence of yeasts, pathogenic fungi, dermatophytes, total coliforms, Escherichia coli and intestinal enterococci in sand. Our results showed that 60.4% of the samples were positive for fungi and that 25.2% were positive for the bacterial parameters. The most frequent fungal species found were Candida sp. and Aspergillus sp., whereas intestinal enterococci were the most frequently isolated bacteria. Positive associations were detected among analyzed parameters and country-regions but none among those parameters and sampling period. Regarding threshold values, we propose 15 cfu/g for yeasts, 17 cfu/g for potential pathogenic fungi, 8 cfu/g for dermatophytes. Twenty-five cfu/g for E. coli, and 10 [corrected] cfu/g for intestinal enterococci.
MeSH term(s)	Arthrodermataceae/isolation & purification ; Bathing Beaches/statistics & numerical data ; Colony Count, Microbial ; Enterococcus/isolation & purification ; Environmental Monitoring ; Escherichia coli/isolation & purification ; Fungi/isolation & purification ; Fungi/pathogenicity ; Geologic Sediments/microbiology ; Portugal ; Risk Assessment ; Seawater/microbiology ; Water Microbiology ; Yeasts/isolation & purification
Language	English
Publishing date	2011-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2001296-2
ISSN	1879-3363 ; 0025-326X
ISSN (online)	1879-3363
ISSN	0025-326X
DOI	10.1016/j.marpolbul.2011.04.008
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Article: Pathogenic fungi: An unacknowledged risk at coastal resorts? New insights on microbiological sand quality in Portugal

Sabino, Raquel / Veríssimo, Cristina / Cunha, Maria Ana / Wergikoski, Bela / Ferreira, Filipa C. / Rodrigues, Raquel / Parada, Helena / Falcão, Leonor / Rosado, Laura / Pinheiro, Catarina / Paixão, Eleonora / Brandão, João

Marine pollution bulletin

Volume v. 62,, Issue no. 7

Abstract	Whilst the potential impact on beach users from microorganisms in water has received considerable attention, there has been relatively little investigation into microbial contaminants in sand. Thirty three beaches across Portugal were analyzed during a five year period (2006–2010) to determine the presence of yeasts, pathogenic fungi, dermatophytes, total coliforms, Escherichia coli and intestinal enterococci in sand. Our results showed that 60.4% of the samples were positive for fungi and that 25.2% were positive for the bacterial parameters. The most frequent fungal species found were Candida sp. and Aspergillus sp., whereas intestinal enterococci were the most frequently isolated bacteria. Positive associations were detected among analyzed parameters and country-regions but none among those parameters and sampling period. Regarding threshold values, we propose 15cfu/g for yeasts, 17cfu/g for potential pathogenic fungi, 8cfu/g for dermatophytes. Eighty four cfu/g for coliforms, 250cfu/g for E. coli, and 100cfu/g for intestinal enterococci.
Keywords	sand ; microbial contamination ; keratinophilic fungi ; Candida ; Aspergillus ; risk ; beaches ; sampling ; Enterococcus ; Escherichia coli ; coliform bacteria ; yeasts ; water pollution
Language	English
Document type	Article
ISSN	0025-326X
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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Article ; Online: Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.

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Article ; Online: PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR.

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Article: Additive Potentiation of R334W-CFTR Function by Novel Small Molecules.

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Article ; Online: Rescue of Mutant CFTR Trafficking Defect by the Investigational Compound MCG1516A.

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Article ; Online: Identification of novel F508del-CFTR traffic correctors among triazole derivatives.

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Article ; Online: Pathogenic fungi: an unacknowledged risk at coastal resorts? New insights on microbiological sand quality in Portugal.

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Article: Pathogenic fungi: An unacknowledged risk at coastal resorts? New insights on microbiological sand quality in Portugal

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