Review
Nutrition & Dietetics
Rosara Bass, Jefferson N. Brownell, Virginia A. Stallings
Summary: Patients with cystic fibrosis face multiple nutritional issues due to CFTR dysfunction, including malnutrition and growth failure. Nutritional interventions targeting these issues have significantly improved patients' nutritional status and clinical outcomes. The advent of highly effective CFTR modulators has revolutionized the care of CF patients.
Article
Biochemistry & Molecular Biology
Mathias Schenkel, Dorna Ravamehr-Lake, Tomasz Czerniak, James P. Saenz, Georg Krainer, Michael Schlierf, Charles M. Deber
Summary: A study found that mutants of cystic fibrosis exhibited folding and helicity similar to the wild type when the corrector VX-809 was added. Fluorescence spectroscopy measurements suggested that the corrector altered lipid packing and water accessibility.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2023)
Article
Chemistry, Medicinal
Emmanuelle Bardin, Alexandra Pastor, Michaela Semeraro, Anita Golec, Kate Hayes, Benoit Chevalier, Farouk Berhal, Guillaume Prestat, Alexandre Hinzpeter, Christine Gravier-Pelletier, Iwona Pranke, Isabelle Sermet-Gaudelus
Summary: Cystic fibrosis is the most frequent life-limiting autosomal recessive disorder in the Caucasian population caused by mutations in the CFTR gene. Current therapies focus on treating the downstream consequences of CFTR mutations, but pharmacologic therapy aims to restore mutated CFTR function and has the potential to transform patient prognosis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Genetics & Heredity
Matthew D. Strub, Long Gao, Kai Tan, Paul B. McCray
Summary: The study demonstrated that miR-138 mimic or SIN3A siRNA could increase Delta F508-CFTR levels and partially restore CFTR-dependent chloride transport. Gene network analysis in CFBE cells revealed that inhibition of NEDD8 and SYVN1 significantly improved Delta F508-CFTR trafficking, maturation, and function.
BMC MEDICAL GENOMICS
(2021)
Article
Chemistry, Multidisciplinary
Jilin Chen, Hongwei Han, Rui Teng, Tong Qin
Summary: This paper proposes a new guidance algorithm based on the saturation function profile to address the control instability issue in aerocapture maneuvers. By simulating the bang-bang control structure and reducing dependence on parameters, the algorithm shows improved robustness and performance.
APPLIED SCIENCES-BASEL
(2022)
Article
Chemistry, Medicinal
Alice Parodi, Giada Righetti, Emanuela Pesce, Annalisa Salis, Valeria Tomati, Cristina Pastorino, Bruno Tasso, Mirko Benvenuti, Gianluca Damonte, Nicoletta Pedemonte, Elena Cichero, Enrico Millo
Summary: This study focuses on the design and testing of new small molecules as CFTR correctors for the treatment of cystic fibrosis. Through molecular modeling and experimental validation, three molecules were identified to have a good efficacy in rescuing the defect of F508del-CFTR. This study provides valuable information for the development of targeted therapies for cystic fibrosis.
Article
Respiratory System
Tzyh-Chang Hwang, Ineke Braakman, Peter van der Sluijs, Isabelle Callebaut
Summary: The loss of function of CFTR protein is the root cause of cystic fibrosis (CF), a common genetic disease. Recent advances in high-throughput drug screening and structural-biology studies have contributed to the development of effective CFTR modulators. This article provides an overview of CFTR folding, function, and pharmacology, with a focus on its first nucleotide-binding domain (NBD1). Understanding the molecular basis of CFTR can inspire the development of mutation-specific CFTR modulators.
JOURNAL OF CYSTIC FIBROSIS
(2023)
Review
Biochemistry & Molecular Biology
Carlos M. Farinha, Martina Gentzsch
Summary: Significant progress has been made in CFTR research, focusing on therapeutic options for cystic fibrosis patients and key molecular interactions of CFTR. Current studies mainly revolve around CFTR folding, processing, and stability interactions, as well as protein complexes and signal pathways regulating CFTR function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Tamara Hillenaar, Jeffrey Beekman, Peter van der Sluijs, Ineke Braakman
Summary: Mutations in CFTR lead to Cystic Fibrosis, and a triple-modulator therapy has been approved for specific mutations. Understanding the biochemical and functional characteristics of the mutations can improve treatment strategies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Carleen Mae Sabusap, Disha Joshi, Luba Simhaev, Kathryn E. Oliver, Hanoch Senderowitz, Marcel van Willigen, Ineke Braakman, Andras Rab, Eric J. Sorscher, Jeong S. Hong
Summary: Patients with cystic fibrosis carrying the P67L variant in CFTR often exhibit typical CF symptoms and show robust response to CFTR correctors. Biochemical measurements and molecular dynamics analysis suggest that the P67L mutation shares key pathogenic features with F508del and may impair the integrity of CFTR structure, providing a potential target for pharmacological repair.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Sharon L. Wong, Nikhil T. Awatade, Miro A. Astore, Katelin M. Allan, Michael J. Carnell, Iveta Slapetova, Po-chia Chen, Alexander Capraro, Laura K. Fawcett, Renee M. Whan, Renate Griffith, Chee Y. Ooi, Serdar Kuyucak, Adam Jaffe, Shafagh A. Waters
Summary: In this study, the characterization of the I37R mutation in the lasso motif of the CFTR chloride channel was conducted. It was found that the I37R-CFTR mutation results in a residual function defect that can be treated with potentiators and type III correctors. This study provides insights into CFTR channel regulation and offers a potential pathway for drug access in CF patients with ultra-rare genotypes.
Article
Physics, Multidisciplinary
Chuanhui Jiang, Honglei Li, Shi-Yuan Li, Shufen Liu, Xinyue Yin
Summary: In the framework of perturbative Quantum Chromodynamics factorization, the production of hadrons involves contributions from fragmentation and combination, with the latter being of higher twist. Particularly, the production of heavy mesons can occur via the combination of a heavy quark with a light one, and the cross section can be factorized as the convolution of the combination matrix element, the light quark distribution function, and the hard partonic sub-cross section of heavy quark production. The partonic distribution and combination matrix element are functions of a scaling variable, which is the momentum fraction of the corresponding quark with respect to the heavy meson. We studied the production of D (*+/-) in jet through combination in pp collisions at the LHC. The overall result is comparable to the experimental data. The combination matrix elements can be further studied in various hadron production processes.
COMMUNICATIONS IN THEORETICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Valeria Capurro, Valeria Tomati, Elvira Sondo, Mario Renda, Anna Borrelli, Cristina Pastorino, Daniela Guidone, Arianna Venturini, Alessandro Giraudo, Sine Mandrup Bertozzi, Ilaria Musante, Fabio Bertozzi, Tiziano Bandiera, Federico Zara, Luis J. V. Galietta, Nicoletta Pedemonte
Summary: The deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most common mutation in cystic fibrosis (CF) patients, and it can be overcome with small molecules called correctors, with VX-445 showing promising efficacy. However, even with corrector combinations, the behavior of F508del-CFTR is not fully normalized, indicating the potential for further improvements in rescuing mutant CFTR.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Physics, Multidisciplinary
M. C. Gandikota, J. M. Schwarz
Summary: During morphogenesis, the featureless convex cerebellum develops folds with thickness varying at different parts. A recent minimal model explained this phenomenon and explored the effects of nonlinear elasticity and steric confinement on shape development. The nonlinear elasticity leads to sharper troughs and wider crests, while steric confinement results in flattening of the crests.
NEW JOURNAL OF PHYSICS
(2021)
Article
Chemistry, Multidisciplinary
Leonardo Bo, Edoardo Milanetti, Cheng Giuseppe Chen, Giancarlo Ruocco, Andrea Amadei, Marco D'Abramo
Summary: The folding-unfolding thermodynamics of two mutants of Trp-cage miniprotein were characterized using extended molecular dynamics simulations and an advanced statistical-mechanical-based approach. The computational data accurately reproduced the experimental results for the thermophilic mutant, but the mesophilic mutant's thermodynamic behavior could not be reconstructed.
Review
Pharmacology & Pharmacy
Miqueias Lopes-Pacheco, Nicoletta Pedemonte, Guido Veit
Summary: Cystic fibrosis is a life-threatening inherited disease caused by mutations in the CFTR gene, with current therapies targeting only symptoms. Novel CFTR modulator drugs are expected to significantly modify the disease course for the majority of patients, with a focus on accelerating drug development and personalized treatment approaches.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Article
Respiratory System
Guido Veit, Christian Vaccarin, Gergely L. Lukacs
Summary: The study found that the combination therapy of VX-445 and VX-770 has significant therapeutic effects on CF patients with the F508del mutation, improving CFTR channel currents. VX-445 has a unique potentiator activity that can enhance the effect of VX-770, especially beneficial for CF patients with G551D and other dual potentiator responsive mutations.
JOURNAL OF CYSTIC FIBROSIS
(2021)
Article
Multidisciplinary Sciences
Haijin Xu, Sandra Isenmann, Tania Lopez-Hernandez, Raul Estevez, Gergely L. Lukacs, Pirjo M. Apaja
Summary: The study reveals the chaperone-like role of GlialCAM in the biosynthetic processing of the MLC1 complex, as well as its regulation of diffusional partitioning and endocytic dynamics of cluster members on the plasma membrane.
SCIENTIFIC REPORTS
(2021)
Article
Health Care Sciences & Services
Guido Veit, Tony Velkov, Haijin Xu, Nathalie Vadeboncoeur, Lara Bilodeau, Elias Matouk, Gergely L. Lukacs
Summary: Trikafta, a triple-combination drug, has shown unprecedented clinical benefits for CF patients with the F508del mutation. The study suggests that introducing a third modulator may not provide additional benefit for patients with certain rare CFTR missense mutations.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Shafqat Rasool, Simon Veyron, Naoto Soya, Mohamed A. Eldeeb, Gergely L. Lukacs, Edward A. Fon, Jean-Francois Trempe
Summary: Mutations in PINK1 lead to Parkinson's disease. The study shows that PINK1 is imported into the translocase of the outer mitochondrial membrane (TOM) complex, leading to its activation by autophosphorylation and initiation of mitochondrial clearance. The crystal structures provide insights into the dimeric autophosphorylation complex and the stabilization mechanism of PINK1 on the core TOM complex.
Article
Biochemistry & Molecular Biology
Hedvig Tordai, Erzsebet Suhajda, Ian Sillitoe, Sreenath Nair, Mihaly Varadi, Tamas Hegedus
Summary: In recent years, the number of unique transmembrane protein structures has doubled, thanks to the advancement of cryo-electron microscopy and AlphaFold2. However, collecting structures for specific protein families remains challenging. This study demonstrates the applicability and usability of automatic collection and presentation of protein structures through the ABC protein superfamily.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Zoltan Hegyi, Tamas Hegedus, Laszlo Homolya
Summary: This study explores the interaction between ABCG1 and ABCG4 isoforms and various sterol compounds. It identifies molecular motifs in ABCG1 that are involved in the interaction with cholesterol. The study also suggests an essential role for the reentry helix in cholesterol sensing in ABCG1.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Daichi Hinata, Ryosuke Fukuda, Tsukasa Okiyoneda
Summary: COPD is a lifestyle-related disease caused by irreversible damage to respiratory tissues from chronic exposure to environmental pollutants, such as cigarette smoke. CFTR polymorphisms (R75Q, M470V) impair the function of CFTR, leading to an excessive proinflammatory response to environmental pathogens associated with COPD. The CF drug Trikafta can correct the CFTR dysfunction and suppress IL-8 production, potentially preventing COPD pathogenesis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Shogo Taniguchi, Ryosuke Fukuda, Tsukasa Okiyoneda
Summary: The CFTR protein is responsible for transporting ions and is regulated by cAMP. Mutations in the CFTR gene result in the genetic disease cystic fibrosis. While most CF-associated mutations lead to the degradation of mutant CFTR proteins, therapeutic agents that allow mutant CFTR to reach the cell membrane are still subject to degradation, reducing their effectiveness. This review discusses the latest understanding of the mechanisms of CFTR degradation and proposes potential new therapeutic strategies for cystic fibrosis.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Article
Biochemistry & Molecular Biology
Kuljeet Singh, Rajesh B. Patil, Vikas Patel, Judit Remenyik, Tamas Hegedus, Katalin Goda
Summary: The human ABCB1 protein plays a crucial role in the pharmacokinetics of chemotherapeutic drugs and drug-drug interactions. It also contributes to chemotherapy resistance in tumor tissues. This study reveals that the combined treatment with quercetin and cyandin-3O-sophroside has a strong inhibitory effect on ABCB1, which may be useful in multidrug-resistant tumors and drug delivery.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Naoto Soya, Haijin Xu, Ariel Roldan, Zhengrong Yang, Haoxin Ye, Fan Jiang, Aiswarya Premchandar, Guido Veit, Susan P. C. Cole, John Kappes, Tamas Hegedus, Gergely L. Lukacs
Summary: The folding and rescuing of multidomain ABC transporters have significant implications for organismal health. In this study, the authors employed molecular dynamic simulations, biochemical and hydrogen deuterium exchange approaches to investigate the mechanisms underlying the folding and rescue of ABCC transporters. It was found that modulating the interfaces between the nucleotide binding domains and transmembrane domains could affect the posttranslational coupled domain-folding in the endoplasmic reticulum. Furthermore, the use of folding correctors could rescue the folding intermediates of CFTR mutants by rewiring inter-domain allosteric networks.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Orsolya Mozner, Boglarka Zambo, Zsuzsa Bartos, Anna Gergely, Kata Sara Szabo, Balint Jezso, Agnes Telbisz, Gyoergy Varady, Laszlo Homolya, Tamas Hegedus, Balazs Sarkadi
Summary: This study analyzed the effects of variants in the unresolved cytoplasmic region of the ABCG2 multidrug transporter on protein function and trafficking. It was found that the K360del variant increased membrane expression and cellular trafficking of ABCG2, while alanine replacements of neighboring lysines had no significant effect on transport function.
Article
Biochemistry & Molecular Biology
Rita Padanyi, Bianka Farkas, Hedvig Tordai, Balint Kiss, Helmut Grubmueller, Naoto Soya, Gergely L. Lukacs, Miklos Kellermayer, Tamas Hegedus
Summary: Cystic fibrosis is a common genetic disease in Caucasians caused by the deletion of F508 in the CFTR gene. Current treatments can partially correct the folding and stability defect, but new pharmacophores are needed to restore the wildtype-like conformational stability of the mutated protein. The molecule BIA can thermally stabilize the NBD1 region and increase its resistance to mechanical unfolding, suggesting its potential as a folding corrector.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Rita Padanyi, Bianka Farkas, Hedvig Tordai, Balint Kiss, Helmut Grubmueller, Naoto Soya, Gergely L. Lukacs, Miklos Kellermayer, Tamas Hegedus
Summary: By employing a combination of molecular dynamics simulations, atomic force spectroscopy, and hydrogendeuterium exchange experiments, researchers investigated the folding dynamics of CFTR protein and its binding mechanism with the compound BIA. They found that BIA could enhance the stability of CFTR protein, suggesting its potential application as a folding corrector in the future.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)