-
International Journal of Molecular... Mar 2020The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic... (Review)
Review
The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic agents such as hypertonic saline and more convincingly with cystic fibrosis transmembrane conductance regulator (CFTR) repair therapies. Although rapidly becoming the standard of care in cystic fibrosis (CF), current CFTR modulators do not treat all patients nor do they restore the rate of decline in lung function to normal levels. As such, novel approaches are still required to ensure all with CF have effective therapies. Although CFTR plays a fundamental role in the regulation of fluid secretion across the airway mucosa, there are other ion channels and transporters that represent viable targets for future therapeutics. In this review article we will summarise the current progress with CFTR-independent approaches to restoring mucosal hydration, including epithelial sodium channel (ENaC) blockade and modulators of SLC26A9. A particular emphasis is given to modulation of the airway epithelial calcium-activated chloride channel (CaCC), TMEM16A, as there is controversy regarding whether it should be positively or negatively modulated. This is discussed in light of a recent report describing for the first time bona fide TMEM16A potentiators and their positive effects upon epithelial fluid secretion and mucus clearance.
Topics: Animals; Anions; Anoctamin-1; Antiporters; Cystic Fibrosis; Drug Discovery; Epithelial Sodium Channels; Humans; Neoplasm Proteins; Respiratory Mucosa; Sulfate Transporters
PubMed: 32235608
DOI: 10.3390/ijms21072386 -
Current Opinion in Chemical Biology Feb 2022Because of the rise in antibiotic resistance and the dwindling pipeline of effective antibiotics, it is imperative to explore avenues that breathe new life into existing... (Review)
Review
Because of the rise in antibiotic resistance and the dwindling pipeline of effective antibiotics, it is imperative to explore avenues that breathe new life into existing drugs. This is particularly important for intrinsically resistant Gram-negative bacteria, which are exceedingly difficult to treat. The Gram-negative outer membrane (OM) prevents the entry of a plethora of antibiotics that are effective against Gram-positive bacteria, despite the presence of the targets of these drugs. Uncovering molecules that increase the permeability of the OM to sensitize Gram-negative bacteria to otherwise ineffective antibiotics is an approach that has recently garnered increased attention in the field. In this review, we survey chemical matter which has been shown to potentiate antibiotics against Gram-negative bacteria by perturbing the OM. These include peptides, nanoparticles, macromolecules, antibiotic conjugates, and small molecules.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria
PubMed: 34808425
DOI: 10.1016/j.cbpa.2021.102099 -
Expert Opinion on Therapeutic Patents 2015Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508... (Review)
Review
INTRODUCTION
Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508 (F508del) is the most common mutation that causes cellular processing, chloride channel gating and protein stability defects in CFTR. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Endeavors in searching F508del-CFTR modulators have shown encouraging results, with several small-molecule compounds having entered clinical trials or even represented clinical options.
AREAS COVERED
This review covers the discovery of F508del-CFTR correctors described in both patents (2005 - present) and scientific literatures.
EXPERT OPINION
Cyclopropane carboxamide derivatives of CFTR correctors continue to dominate in this area, among which lumacaftor (a NBD1-MSD1/2 interface stabilizer) is the most promising compound and is now under the priority review by US FDA. However, the abrogation effect of ivacaftor (potentiator) on lumacaftor suggests the requirement of discovering new correctors and potentiators that can cooperate well. Integration screening for simultaneously identifying combinations of correctors (particularly NBD1 stabilizer) and potentiators should provide an alternative strategy. A recently reported natural product fraction library may be useful for the integration screening.
Topics: Aminophenols; Aminopyridines; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Design; Humans; Mutation; Patents as Topic; Quinolones
PubMed: 25971311
DOI: 10.1517/13543776.2015.1045878 -
European Journal of Medicinal Chemistry Jan 2021We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770...
We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC ∼600 nM representing an ∼17-fold improvement over the original compound identified in a small molecule screen.
Topics: Aminophenols; Animals; Cell Line; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Indoles; Models, Molecular; Mutation; Piperidines; Quinolones; Rats; Structure-Activity Relationship
PubMed: 33092904
DOI: 10.1016/j.ejmech.2020.112888 -
Behavioural Brain Research Apr 2022Previous studies have demonstrated a close association between α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) and depressive disorders, and...
Previous studies have demonstrated a close association between α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) and depressive disorders, and activation of AMPARs may represent a promising way to treat depression. However, the effects of AMPAR potentiators on depression and the underlying mechanism have not been comprehensively clarified. We used lipopolysaccharide (LPS) to establish a depressive mouse model and an in vitro damage model of SH-SY5Y cells, and the AMPAR potentiator LY450108 was introduced to the study. We found that LY450108 alleviated LPS-induced depressive behavior and abnormal phosphorylation of hippocampal AMPARs in mice. LY450108 also alleviated LPS-induced apoptosis and decreased the viability of SH-SY5Y cells. In addition, LY450108 protected SH-SY5Y cells from LPS-induced abnormal phosphorylation of AMPARs. In conclusion, our findings suggest that LY450108 has antidepressant effects against LPS-induced neuronal damage and depression.
Topics: Animals; Antidepressive Agents; Disease Models, Animal; Hippocampus; Lipopolysaccharides; Mice; Receptors, AMPA
PubMed: 35202718
DOI: 10.1016/j.bbr.2022.113813 -
Drug Discoveries & Therapeutics Dec 2022A cell-based assay was conducted to screen microbial culture broths for potentiators of neutral lipid degradation in Chinese Hamster Ovary K1 cells. A total of 5,363...
A cell-based assay was conducted to screen microbial culture broths for potentiators of neutral lipid degradation in Chinese Hamster Ovary K1 cells. A total of 5,363 microbial cultures from fungi and actinomycetes were screened in this assay. Brefeldin A (1) from fungal cultures was found to promote the degradation of triacylglycerol (TG) with an EC of 2.6 µM. Beauveriolides I (2), III (3), beauverolides A (4), B (5), and K (6) from fungal cultures showed potentiating effect on cholesteryl ester (CE) degradation with ECs ranging from 0.02 to 0.13 µM. Among these compounds, 2 and 6 exhibited the strongest activities (EC, 0.02 µM). From actinomycete cultures, oxohygrolidin (7) (EC for TG and CE, > 1.7 and 0.8 µM, respectively) and hygrolidin (8) (EC for TG and CE, 0.08 and 0.004 µM, respectively) promoted degradation of CE more preferably than TG.
Topics: Cricetinae; Animals; Cricetulus; CHO Cells; Fungi; Lipids; Triglycerides
PubMed: 36450503
DOI: 10.5582/ddt.2022.01087 -
ACS Infectious Diseases May 2022Combination therapy with membrane-targeting compounds is at the forefront because the bacterial membrane is an attractive target considering its role in various...
Combination therapy with membrane-targeting compounds is at the forefront because the bacterial membrane is an attractive target considering its role in various multidrug-resistant elements. However, this strategy is crippled by the toxicity associated with these agents. The structural requirements for optimum membrane perturbation and minimum toxicity have not been explored for membrane-targeting antibiotic potentiators or adjuvants. Here, we report the structural influence of different chemical moieties on membrane perturbation, activity, toxicity, and potentiating ability in norspermidine derivatives. It has been shown in this report that weak membrane perturbation, achieved by the incorporation of cyclic hydrophobic moieties, is an effective strategy to design antibiotic adjuvants with negligible toxicity and activity but good potentiating ability. Aryl or adamantane functionalized derivatives were found to be better resorts as opposed to the acyclic analogues, exhibiting as high as 4096-fold potentiation of multiple classes of antibiotics toward critical Gram-negative superbugs. The mechanism of potentiation was nonspecific, consisting of weak outer-membrane permeabilization, membrane depolarization, and efflux inhibition. This unique concept of "weakly perturbing the membrane" by incorporating cyclic hydrophobic moieties in a chemical design with free amine groups serves as a breakthrough for nontoxic membrane-perturbing adjuvants and has the potential to revitalize the effect of obsolete antibiotics to treat complicated Gram-negative bacterial infections.
Topics: Adjuvants, Pharmaceutic; Anti-Bacterial Agents; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans
PubMed: 35404568
DOI: 10.1021/acsinfecdis.2c00092 -
Acta Naturae 2017The interaction of TRPV1-receptors agonists (capsaicin and protons) has been studied on cultured CHO cells transfected by TRPV1-receptors. Using the whole-cell...
The interaction of TRPV1-receptors agonists (capsaicin and protons) has been studied on cultured CHO cells transfected by TRPV1-receptors. Using the whole-cell patch-clamp approach, it was shown that summation of the currents induced by agonist application was dependent on the membrane potential. The TRPV1-mediated currents induced by the pH and Capsaicin demonstrated arithmetical summation at potentials between 40--40 mV, while they were potentiated at potentials below -40 mV. Currents induced by the pH and Capsaicin combined were higher in comparison with the arithmetic sum of the currents induced by the pH and Capsaicin applied separately at such potentials. Such a potential dependence seems to be a base of the sensitization that is induced by inflammation or pain, when concentrations of proinflammatory mediators acting as TRPV1 agonists are increasing. Further depolarization induced by TRPV1 activation doesn't generate potentiation, which might serve as a protective mechanism to restrict their activity.
PubMed: 28461977
DOI: No ID Found -
The Journal of General Physiology Jun 2024Cannabidiol (CBD), the main non-psychotropic phytocannabinoid produced by the Cannabis sativa plant, blocks a variety of cardiac ion channels. We aimed to identify...
Cannabidiol (CBD), the main non-psychotropic phytocannabinoid produced by the Cannabis sativa plant, blocks a variety of cardiac ion channels. We aimed to identify whether CBD regulated the cardiac pacemaker channel or the hyperpolarization-activated cyclic nucleotide-gated channel (HCN4). HCN4 channels are important for the generation of the action potential in the sinoatrial node of the heart and increased heart rate in response to β-adrenergic stimulation. HCN4 channels were expressed in HEK 293T cells, and the effect of CBD application was examined using a whole-cell patch clamp. We found that CBD depolarized the V1/2 of activation in holo-HCN4 channels, with an EC50 of 1.6 µM, without changing the current density. CBD also sped activation kinetics by approximately threefold. CBD potentiation of HCN4 channels occurred via binding to the closed state of the channel. We found that CBD's mechanism of action was distinct from cAMP, as CBD also potentiated apo-HCN4 channels. The addition of an exogenous PIP2 analog did not alter the ability of CBD to potentiate HCN4 channels, suggesting that CBD also acts using a unique mechanism from the known HCN4 potentiator PIP2. Lastly, to gain insight into CBD's mechanism of action, computational modeling and targeted mutagenesis were used to predict that CBD binds to a lipid-binding pocket at the C-terminus of the voltage sensor. CBD represents the first FDA-approved drug to potentiate HCN4 channels, and our findings suggest a novel starting point for drug development targeting HCN4 channels.
Topics: Cannabidiol; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; HEK293 Cells; Potassium Channels; Ion Channel Gating; Muscle Proteins
PubMed: 38652080
DOI: 10.1085/jgp.202313505 -
European Journal of Applied Physiology May 2024Post-activation potentiation (PAP) describes the enhancement of twitch torque following a conditioning contraction (CC) in skeletal muscle. In adults, PAP may be related...
BACKGROUND
Post-activation potentiation (PAP) describes the enhancement of twitch torque following a conditioning contraction (CC) in skeletal muscle. In adults, PAP may be related to muscle fibre composition and is accompanied by a decrease in motor unit (MU) firing rates (MUFRs). Muscle fibre composition and/or activation is different between children and adults. This study examined PAP and MU firing patterns of the potentiated knee extensors in boys and men.
METHODS
Twenty-three boys (10.5 ± 1.3 years) and 20 men (23.1 ± 3.3 years) completed familiarization and experimental sessions. Maximal isometric evoked-twitch torque and MU firing patterns during submaximal contractions (20% and 70% maximal voluntary isometric contraction, MVIC) were recorded before and after a CC (5 s MVIC). PAP was calculated as the percent-increase in evoked-twitch torque after the CC. MU firing patterns were examined during submaximal contractions before and after the CC using Trigno Galileo surface electrodes (Delsys Inc) and decomposition algorithms (NeuroMap, Delsys Inc). MU action potential amplitudes (MUAPamp) and MUFRs were calculated for each MU and exponential MUFR-MUAPamp relationships were calculated for each participant and trial.
RESULTS
PAP was higher in men than in boys (98.3 ± 37.1% vs. 68.8 ± 18.3%, respectively; p = 0.002). Following potentiation, the rate of decay of the MUFR-MUAPamps relationship decreased in both contractions, with a greater decrease among boys during the high-intensity contractions.
CONCLUSION
Lower PAP in the boys did not coincide with smaller changes in potentiated MU firing patterns, as boys had greater reductions in MUFRs with potentiation compared with men in high-intensity contractions.
Topics: Humans; Male; Child; Isometric Contraction; Muscle, Skeletal; Torque; Adult; Young Adult; Action Potentials; Motor Neurons
PubMed: 38159138
DOI: 10.1007/s00421-023-05377-z