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Cell May 2024The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
PubMed: 38810646
DOI: 10.1016/j.cell.2024.04.046 -
Revue Medicale Suisse Jun 2020Cystic Fibrosis is a genetic disorder resulting in the absence or dysfunction of the CFTR protein, a chloride channel present on the surface of epithelia, particularly... (Review)
Review
Cystic Fibrosis is a genetic disorder resulting in the absence or dysfunction of the CFTR protein, a chloride channel present on the surface of epithelia, particularly respiratory. Until recently, treatments only concerned the consequences of the disease. But a new type of molecules called « modulators », is already available to some patients and targets the origin of the disease. « Modulators » are divided into « potentiators », which improve the transport of chloride by the CFTR protein, and « correctors », increasing the amount of CFTR proteins. An oral triple therapy combining a potentiator and two correctors has just been approved in the USA and will treat 85 % of patients. The clinical benefit of « modulators » is remarkable, and these drugs are revolutionizing the treatment of Cystic Fibrosis.
Topics: Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation
PubMed: 32558451
DOI: No ID Found -
Trends in Neurosciences Mar 2016At excitatory and inhibitory synapses, an immediate transfer of additional neurotransmitter receptors from non-synaptic positions to the synapse mediates synaptic... (Review)
Review
At excitatory and inhibitory synapses, an immediate transfer of additional neurotransmitter receptors from non-synaptic positions to the synapse mediates synaptic long-term potentiation (LTP). Different types of non-synaptic reserve pools permit the rapid supply of transmembrane neurotransmitter receptors. Recycling endosomes (REs) serve as an intracellular reservoir of receptors that is delivered to the plasma membrane on LTP induction. Furthermore, AMPA receptors at the non-synaptic plasma membrane provide an extrasynaptic reserve pool that is also important to potentiate synapse function. Finally, bidirectional synaptic versus extrasynaptic trapping of freely diffusing plasma membrane GABAA receptors (GABAARs) by scaffolding proteins modulates synaptic transmission. Here we discuss novel findings regarding neurotransmitter receptor reservoirs and potential reserve pool mechanisms for synaptic potentiation.
Topics: Animals; Receptors, Neurotransmitter; Synapses; Synaptic Potentials
PubMed: 26833258
DOI: 10.1016/j.tins.2016.01.002 -
Sports Medicine (Auckland, N.Z.) Jun 2016This review article discusses previous postactivation potentiation (PAP) literature and provides a deterministic model for vertical jump (i.e., squat jump,... (Review)
Review
This review article discusses previous postactivation potentiation (PAP) literature and provides a deterministic model for vertical jump (i.e., squat jump, countermovement jump, and drop/depth jump) potentiation. There are a number of factors that must be considered when designing an effective strength-power potentiation complex (SPPC) focused on vertical jump potentiation. Sport scientists and practitioners must consider the characteristics of the subject being tested and the design of the SPPC itself. Subject characteristics that must be considered when designing an SPPC focused on vertical jump potentiation include the individual's relative strength, sex, muscle characteristics, neuromuscular characteristics, current fatigue state, and training background. Aspects of the SPPC that must be considered for vertical jump potentiation include the potentiating exercise, level and rate of muscle activation, volume load completed, the ballistic or non-ballistic nature of the potentiating exercise, and the rest interval(s) used following the potentiating exercise. Sport scientists and practitioners should design and seek SPPCs that are practical in nature regarding the equipment needed and the rest interval required for a potentiated performance. If practitioners would like to incorporate PAP as a training tool, they must take the athlete training time restrictions into account as a number of previous SPPCs have been shown to require long rest periods before potentiation can be realized. Thus, practitioners should seek SPPCs that may be effectively implemented in training and that do not require excessive rest intervals that may take away from valuable training time. Practitioners may decrease the necessary time needed to realize potentiation by improving their subject's relative strength.
Topics: Athletic Performance; Humans; Movement; Muscle Strength; Muscle, Skeletal; Physical Conditioning, Human; Plyometric Exercise; Rest; Sex Factors; Time Factors; Weight-Bearing
PubMed: 26712510
DOI: 10.1007/s40279-015-0466-9 -
MedChemComm Feb 2018Vaccines show great potential for both prophylactic and therapeutic use in infections, cancer, and other diseases. With the rapid development of bio-technologies and... (Review)
Review
Vaccines show great potential for both prophylactic and therapeutic use in infections, cancer, and other diseases. With the rapid development of bio-technologies and materials sciences, nanomaterials are playing essential roles in novel vaccine formulations and can boost antigen effectiveness by operating as delivery systems to enhance antigen processing and/or as immune-potentiating adjuvants to induce or potentiate immune responses. The effect of nanoparticles in vaccinology showed enhanced antigen stability and immunogenicity as well as targeted delivery and slow release. However, obstacles remain due to the lack of fundamental knowledge on the detailed molecular working mechanism and bio-effects of nanoparticles. This review provides a broad overview of the current improvements in nanoparticles in vaccinology. Modern nanoparticle vaccines are classified by the nanoparticles' action based on either delivery system or immune potentiator approaches. The mechanisms of interaction of nanoparticles with the antigens and the immune system are discussed. Nanoparticle vaccines approved for use are also listed. A fundamental understanding of the bio-distribution and the fate of nanoparticles will accelerate the rational design of new nanoparticles comprising vaccines in the future.
PubMed: 30108916
DOI: 10.1039/c7md00158d -
Cells Nov 2021Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection... (Review)
Review
Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit cystic fibrosis patients.
Topics: Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Inflammation; Lung; Translational Research, Biomedical; Treatment Outcome
PubMed: 34831482
DOI: 10.3390/cells10113260 -
Frontiers in Pediatrics 2020Cystic fibrosis is the most common life-shortening genetic disease affecting Caucasians, clinically manifested by fat malabsorption, poor growth and nutrition, and... (Review)
Review
Cystic fibrosis is the most common life-shortening genetic disease affecting Caucasians, clinically manifested by fat malabsorption, poor growth and nutrition, and recurrent sinopulmonary infections. Newborn screening programs for cystic fibrosis are now implemented throughout the United States and in many nations worldwide. Early diagnosis and interventions have led to improved clinical outcomes for people with cystic fibrosis. Newer cystic fibrosis transmembrane conductance regulator potentiators and correctors with mutation-specific effects have increasingly been used in children, and these agents are revolutionizing care. Indeed, it is possible that highly effective modulator therapy used early in life could profoundly affect the trajectory of cystic fibrosis lung disease, and primary prevention may be achievable.
PubMed: 33505947
DOI: 10.3389/fped.2020.608821 -
Biochemical Pharmacology Jul 2017Maintaining the integrity of cellular membranes is critical to protecting metabolic activities and genetic information from the environment. Regulation of transport... (Review)
Review
Maintaining the integrity of cellular membranes is critical to protecting metabolic activities and genetic information from the environment. Regulation of transport across membranes of essential chemicals, including water, nutrients, hormones and many drugs, is therefore key to cellular homeostasis and physiological processes. The two main transporter superfamilies are ATP-binding cassette (ABC) transporters that primarily function as efflux transporters, and the solute carrier (SLC) transporters. SLC transporters encompass 52 gene families with almost 400 different human transporter genes. Although long under-explored, SLC transporters are an emerging drug target class and the molecular target of several approved inhibitor drugs, such as selective serotonin reuptake inhibitors (SSRIs) for depression and sodium/glucose co-transporter (SGLT2) inhibitors for diabetes. Interestingly though, although loss-of-function mutations in numerous human SLC transporters are linked to Mendelian diseases, few reports of SLC transporter activators have appeared, and only inhibitors have been advanced to clinical studies. In this commentary, we discuss several strategies for potentiating SLC transporter function, from direct acting potentiators to modulators of transcription, translation or trafficking. We review the progress made in recent years toward the understanding of the structural and molecular basis of SLC transporter function and the pathways and mechanisms that regulate SLC expression, and describe the opportunities these new insights present for discovery of SLC transporter potentiators. Finally, we highlight the challenges associated with the various approaches and provide some thoughts on future directions that might facilitate the search for SLC potentiators with therapeutic potential.
Topics: Animals; Biological Transport; Cell Membrane; Drug Discovery; Humans; Membrane Transport Proteins; Protein Structure, Secondary; Protein Structure, Tertiary; Protein Transport; Selective Serotonin Reuptake Inhibitors; Solute Carrier Proteins
PubMed: 28214518
DOI: 10.1016/j.bcp.2017.02.010 -
ELife Dec 2021Learning requires neural adaptations thought to be mediated by activity-dependent synaptic plasticity. A relatively non-standard form of synaptic plasticity driven by...
Learning requires neural adaptations thought to be mediated by activity-dependent synaptic plasticity. A relatively non-standard form of synaptic plasticity driven by dendritic calcium spikes, or plateau potentials, has been reported to underlie place field formation in rodent hippocampal CA1 neurons. Here, we found that this behavioral timescale synaptic plasticity (BTSP) can also reshape existing place fields via bidirectional synaptic weight changes that depend on the temporal proximity of plateau potentials to pre-existing place fields. When evoked near an existing place field, plateau potentials induced less synaptic potentiation and more depression, suggesting BTSP might depend inversely on postsynaptic activation. However, manipulations of place cell membrane potential and computational modeling indicated that this anti-correlation actually results from a dependence on current synaptic weight such that weak inputs potentiate and strong inputs depress. A network model implementing this bidirectional synaptic learning rule suggested that BTSP enables population activity, rather than pairwise neuronal correlations, to drive neural adaptations to experience.
Topics: Action Potentials; Animals; Computer Simulation; Dendrites; Female; Hippocampus; Learning; Male; Mice; Neuronal Plasticity; Neurons; Synapses
PubMed: 34882093
DOI: 10.7554/eLife.73046 -
Pediatric Pulmonology Feb 2021Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease... (Review)
Review
Since the discovery of the gene responsible for cystic fibrosis (CF) in 1989, hopes have been pinned on a future with novel therapies tackling the basis of the disease rather than its symptoms. These have become a reality over the last decade with the development through to the clinic of CF transmembrane conductance regulator (CFTR) modulators. These are oral drugs which improve CFTR protein function through either increasing the time the channel pore is open (potentiators) or facilitating its trafficking through the cell to its location on the cell membrane (correctors). The first potentiator, ivacaftor, is now licensed and available clinically in many parts of the world. It is highly effective with impressive clinical impact in the lungs and gastrointestinal tract; longer-term data from patient registries show fewer exacerbations, a slower rate of lung function loss and reduced need for transplantation in patients receiving ivacaftor. However, as a single drug, it is suitable for only a small minority of patients. The commonest CFTR mutation, F508del, requires both correction and potentiation for clinical efficacy. Two dual-agent drugs (lumacaftor/ivacaftor and tezacaftor/ivacaftor) have progressed through to licensing, although their short term impact is more modest than that of ivacaftor; this is likely due to only partial correction of protein misfolding and trafficking. Most recently, triple compounds have been developed: two different corrector molecules (elexacaftor and tezacaftor) which, by addressing different regions in the misfolded F508del protein, more effectively improve trafficking. In addition to large improvements in clinical outcomes in people with two copies of F508del, the combination is sufficiently effective that it works in patients with only one copy of F508del and a second, nonmodulator responsive mutation. For the first time, we thus have a drug suitable for around 85% of people with CF. Even more gains are likely to be possible when these drugs can be used in younger children, although more sensitive outcome measures are needed for this age group. Special consideration is needed for people with very rare mutations; those with nonmodulatable mutation combinations will likely require gene or messenger RNA-based therapeutic approaches, many of which are being explored. Although this progress is hugely to be celebrated, we still have more work to do. The international collaboration between trials networks, pharma, patient organizations, registries, and people with CF is something we are all rightly proud of, but innovative trial design and implementation will be needed if we are to continue to build on this progress and further develop drugs for people with CF.
Topics: Aminophenols; Aminopyridines; Benzodioxoles; Child; Chloride Channel Agonists; Clinical Trials as Topic; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Therapy, Combination; Humans; Indoles; Mutation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones
PubMed: 33434412
DOI: 10.1002/ppul.24968