Статті в журналах: "Potentiators"

1

Cui, Guiying, and Nael A. McCarty. "Murine and human CFTR exhibit different sensitivities to CFTR potentiators." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 7 (October 1, 2015): L687—L699. http://dx.doi.org/10.1152/ajplung.00181.2015.

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Development of therapeutic molecules with clinical efficacy as modulators of defective CFTR includes efforts to identify potentiators that can overcome or repair the gating defect in mutant CFTR channels. This has taken a great leap forward with the identification of the potentiator VX-770, now available to patients as “Kalydeco.” Other small molecules with different chemical structure also are capable of potentiating the activity of either wild-type or mutant CFTR, suggesting that there are features of the protein that may be targeted to achieve stimulation of channel activity by structurally diverse compounds. However, neither the mechanisms by which these compounds potentiate mutant CFTR nor the site(s) where these compounds bind have been identified. This knowledge gap partly reflects the lack of appropriate experimental models to provide clues toward the identification of binding sites. Here, we have compared the channel behavior and response to novel and known potentiators of human CFTR (hCFTR) and murine (mCFTR) expressed in Xenopus oocytes. Both hCFTR and mCFTR were blocked by GlyH-101 from the extracellular side, but mCFTR activity was increased with GlyH-101 applied directly to the cytoplasmic side. Similarly, glibenclamide only exhibited a blocking effect on hCFTR but both blocked and potentiated mCFTR in excised membrane patches and in intact oocytes. The clinically used CFTR potentiator VX-770 transiently increased hCFTR by ∼13% but potentiated mCFTR significantly more strongly. Our results suggest that mCFTR pharmacological sensitivities differ from hCFTR, which will provide a useful tool for identifying the binding sites and mechanism for these potentiators.

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2

Fowler, Jill H., Katherine Whalley, Tracey Murray, Michael J. O'Neill, and James McCulloch. "The AMPA Receptor Potentiator LY404187 Increases Cerebral Glucose Utilization and c-fos Expression in the Rat." Journal of Cerebral Blood Flow & Metabolism 24, no. 10 (October 2004): 1098–109. http://dx.doi.org/10.1097/01.wcb.0000138665.25305.7c.

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AMPA receptor potentiators enhance AMPA receptor-mediated glutamatergic neurotransmission and may have therapeutic potential as cognitive enhancers or antidepressants. The anatomical basis for the action of AMPA receptor potentiators is unknown. The aim of this study was to determine the effects of the biarylpropylsulfonamide AMPA receptor potentiator, LY404187 (0.05 to 5 mg/kg subcutaneously), upon cerebral glucose utilization and c-fos expression using 14C-2-deoxglucose autoradiography and c-fos immunocytochemistry. LY404187 (0.5 mg/kg) produced significant elevations in glucose utilization in 28 of the 52 anatomical regions analyzed, which included rostral neocortical areas and the hippocampus, as well the dorsal raphe nucleus, lateral habenula, and locus coeruleus. No significant decreases in glucose utilization were observed in any region after LY404187 administration. The increases in glucose utilization with LY404187 (0.5 mg/kg) were blocked by pretreatment with the AMPA receptor antagonist LY293558 (25 mg/kg), indicating that LY404187 acts through AMPA receptor-mediated mechanisms. LY404187 (0.5 mg/kg) also produced increases in c-fos immunoreactivity in the cortex, locus coeruleus, and the dorsal raphe nucleus. These studies demonstrate neuronal activation in key brain areas that are associated with memory processes and thus provide an anatomical basis for the cognitive enhancing effects of AMPA receptor potentiators.

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3

Righetti, Giada, Monica Casale, Michele Tonelli, Nara Liessi, Paola Fossa, Nicoletta Pedemonte, Enrico Millo, and Elena Cichero. "New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach." Pharmaceuticals 13, no. 12 (December 4, 2020): 445. http://dx.doi.org/10.3390/ph13120445.

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Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π–π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators.

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4

Favia, Maria, Maria T. Mancini, Valentino Bezzerri, Lorenzo Guerra, Onofrio Laselva, Anna C. Abbattiscianni, Lucantonio Debellis, et al. "Trimethylangelicin promotes the functional rescue of mutant F508del CFTR protein in cystic fibrosis airway cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 307, no. 1 (July 1, 2014): L48—L61. http://dx.doi.org/10.1152/ajplung.00305.2013.

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Cystic fibrosis transmembrane conductance regulator (CFTR) carrying the F508del mutation is retained in endoplasmic reticulum and fails to traffic to the cell surface where it functions as a protein kinase A (PKA)-activated chloride channel. Pharmacological correctors that rescue the trafficking of F508del CFTR may overcome this defect; however, the rescued F508del CFTR still displays reduced chloride permeability. Therefore, a combined administration of correctors and potentiators of the gating defect is ideal. We recently found that 4,6,4′-trimethylangelicin (TMA), besides inhibiting the expression of the IL-8 gene in airway cells in which the inflammatory response was challenged with Pseudomonas aeruginosa, also potentiates the cAMP/PKA-dependent activation of wild-type CFTR or F508del CFTR that has been restored to the plasma membrane. Here, we demonstrate that long preincubation with nanomolar concentrations of TMA is able to effectively rescue both F508del CFTR-dependent chloride secretion and F508del CFTR cell surface expression in both primary or secondary airway cell monolayers homozygous for F508del mutation. The correction effect of TMA seems to be selective for CFTR and persisted for 24 h after washout. Altogether, the results suggest that TMA, besides its anti-inflammatory and potentiator activities, also displays corrector properties.

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5

Bacalhau, Mafalda, Filipa C. Ferreira, Iris A. L. Silva, Camilla D. Buarque, Margarida D. Amaral, and Miquéias Lopes-Pacheco. "Additive Potentiation of R334W-CFTR Function by Novel Small Molecules." Journal of Personalized Medicine 13, no. 1 (January 1, 2023): 102. http://dx.doi.org/10.3390/jpm13010102.

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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.

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6

Pedemonte, Nicoletta, Valeria Tomati, Elvira Sondo, and Luis J. V. Galietta. "Influence of cell background on pharmacological rescue of mutant CFTR." American Journal of Physiology-Cell Physiology 298, no. 4 (April 2010): C866—C874. http://dx.doi.org/10.1152/ajpcell.00404.2009.

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Cystic fibrosis (CF) is caused by mutations in the CFTR chloride channel. Deletion of phenylalanine 508 (F508del), the most frequent CF mutation, impairs the maturation and gating of the CFTR protein. Such defects may be corrected in vitro by pharmacological modulators named as correctors and potentiators, respectively. We have evaluated a panel of correctors and potentiators derived from various sources to assess potency, efficacy, and mechanism of action. For this purpose, we have used functional and biochemical assays on two different cell expression systems, Fischer rat thyroid (FRT) and A549 cells. The order of potency and efficacy of potentiators was similar in the two cell types considered, with phenylglycine PG-01 and isoxazole UCCF-152 being the most potent and least potent, respectively. Most potentiators were also effective on two mutations, G551D and G1349D, that cause a purely gating defect. In contrast, corrector effect was strongly affected by cell background, with the extreme case of many compounds working in one cell type only. Our findings are in favor of a direct action of potentiators on CFTR, possibly at a common binding site. In contrast, most correctors seem to work indirectly with various mechanisms of action. Combinations of correctors acting at different levels may lead to additive F508del-CFTR rescue.

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7

Mancini, Giulia, Nicoletta Loberto, Debora Olioso, Maria Cristina Dechecchi, Giulio Cabrini, Laura Mauri, Rosaria Bassi, et al. "GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease." International Journal of Molecular Sciences 21, no. 12 (June 24, 2020): 4486. http://dx.doi.org/10.3390/ijms21124486.

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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.

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8

Basta, Karol, and Chris John. "Combination Correctors and Potentiators for Cystic Fibrosis." Physician 6, no. 1 (November 27, 2019): c7. http://dx.doi.org/10.38192/1.6.1.c7.

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The most common cause of cystic fibrosis (CF) is the Phe508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting in CFTR’s reduced trafficking, targeted by correctors, and reduced functioning, targeted by potentiators. For the majority of CF patients, the combination correctors and potentiators (CCPs) lumacaftor/ivacaftor and tezacaftor/ivacaftor, are the only treatments licensed to target the disease origin.

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9

Cuyx, Senne, and Kris De Boeck. "Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis." Seminars in Respiratory and Critical Care Medicine 40, no. 06 (October 28, 2019): 762–74. http://dx.doi.org/10.1055/s-0039-1696664.

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AbstractDetailed knowledge of how mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disturb the trafficking or function of the CFTR protein and the use of high-throughput drug screens have allowed novel therapeutic strategies for cystic fibrosis (CF). The main goal of treatment is slowly but surely shifting from symptomatic management to targeting the underlying CFTR defect to halt disease progression and even to prevent occurrence of CF complications. CFTR potentiators for patients with class III mutations, mutation R117H (and in United States also for patients with specific residual function mutations) and the combination of a CFTR modulator plus a potentiator for patients homozygous for F508del, are the two classes of modulators that are in use in the clinic. Approval of these therapeutics has progressively expanded to include both younger patients and a wider range of CFTR mutations. For a significant proportion of patients with CF, current treatment is however still insufficient or unavailable.This review provides an overview of the clinical trial results and the real-life efficacy data of approved CFTR modulators. In addition, we discuss the entire pipeline of CFTR modulators: novel potentiators and correctors, amplifiers, stabilizers, and read-through agents. Furthermore, we discuss other strategies to improve CFTR function like nonsense-mediated decay inhibitors, modified transfer ribonucleic acids, antisense oligonucleotides, and genetic therapies.CFTR modulators are already changing the face of CF and the pipeline of new therapies continues to be exciting.

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10

Mareux, Elodie, Martine Lapalus, Amel Ben Saad, Renaud Zelli, Mounia Lakli, Yosra Riahi, Marion Almes, et al. "In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators." International Journal of Molecular Sciences 23, no. 18 (September 15, 2022): 10758. http://dx.doi.org/10.3390/ijms231810758.

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ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the ABCB11 gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/Slc10A1). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter.

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11

Johnson, M. P., E. S. Nisenbaum, T. H. Large, R. Emkey, M. Baez, and A. E. Kingston. "Allosteric modulators of metabotropic glutamate receptors: lessons learnt from mGlu1, mGlu2 and mGlu5 potentiators and antagonists." Biochemical Society Transactions 32, no. 5 (October 26, 2004): 881–87. http://dx.doi.org/10.1042/bst0320881.

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Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

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12

Cook, David J., and Coral F. Tudball. "Potentiators and bolus intravenous furosemide." Lancet 358, no. 9290 (October 2001): 1373–74. http://dx.doi.org/10.1016/s0140-6736(01)06443-1.

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13

Chermensky, A. G., T. E. Gembitskaya, A. V. Orlov, and V. R. Makhmutova. "The use of targeted therapy lumacaftor/ivacaftor in patients with cystic fibrosis." Meditsinskiy sovet = Medical Council, no. 4 (April 6, 2022): 98–106. http://dx.doi.org/10.21518/2079-701x-2022-16-4-98-106.

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Accepted, basic therapy of cystic fibrosis (CF), until recently, was symptomatic and aimed at slowing down pathological processes, mainly from the respiratory system and gastrointestinal tract, caused by a defect in the CFTR gene. New strategic opportunities have emerged since 2012 and are aimed at correcting a defect in a gene or its product. A mutation in the cystic fibrosis gene disrupts the function of the cystic fibrosis transmembrane conductance regulator protein (CFTR or CFTR in English transcription), which is located on the surface of the apical membrane of epithelial cells and functions as a chloride channel. The basic achievement for the new CF therapy was the discovery of small molecules that restore the processes of synthesis, transport to the membrane, or the functioning of the defective CFTR protein. The effectiveness of drugs that restore CFTR function is related to the ability of the molecules to deliver an adequate amount of the CFTR protein to the surface of the epithelial cell and/or improve its functional activity. Among them, correctors and potentiators for pharmacological modulation of ion transport are distinguished in clinical practice. Correctors are medicinal substances that allow the mutant CFTR protein to pass through the system of intracellular quality control and take the correct location on the apical membrane (with class II mutations). The action of potentiators is aimed at restoring (activating) the function of the ion channel formed by the mutant CFTR protein (class III–IV mutations). The purpose of this article is to analyze the literature sources, the results of clinical trials on the use of CFTR modulators, including combinations of a potentiator and a corrector. Their effectiveness and safety were evaluated. Literature sources (20) are used and own clinical observation is given. A positive assessment of the action of the modulator, the combination of a potentiator and a corrector, its safety and good tolerability is given. In conclusion, the place and indications for prescribing drugs of this class, the number of patients in the Russian Federation in need of such treatment are determined.

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14

Cui, Guiying, Netaly Khazanov, Brandon B. Stauffer, Daniel T. Infield, Barry R. Imhoff, Hanoch Senderowitz, and Nael A. McCarty. "Potentiators exert distinct effects on human, murine, and Xenopus CFTR." American Journal of Physiology-Lung Cellular and Molecular Physiology 311, no. 2 (August 1, 2016): L192—L207. http://dx.doi.org/10.1152/ajplung.00056.2016.

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VX-770 (Ivacaftor) has been approved for clinical usage in cystic fibrosis patients with several CFTR mutations. Yet the binding site(s) on CFTR for this compound and other small molecule potentiators are unknown. We hypothesize that insight into this question could be gained by comparing the effect of potentiators on CFTR channels from different origins, e.g., human, mouse, and Xenopus (frog). In the present study, we combined this comparative molecular pharmacology approach with that of computer-aided drug discovery to identify and characterize new potentiators of CFTR and to explore possible mechanism of action. Our results demonstrate that 1) VX-770, NPPB, GlyH-101, P1, P2, and P3 all exhibited ortholog-specific behavior in that they potentiated hCFTR, mCFTR, and xCFTR with different efficacies; 2) P1, P2, and P3 potentiated hCFTR in excised macropatches in a manner dependent on the degree of PKA-mediated stimulation; 3) P1 and P2 did not have additive effects, suggesting that these compounds might share binding sites. Also 4) using a pharmacophore modeling approach, we identified three new potentiators (IOWH-032, OSSK-2, and OSSK-3) that have structures similar to GlyH-101 and that also exhibit ortholog-specific potentiation of CFTR. These could potentially serve as lead compounds for development of new drugs for the treatment of cystic fibrosis. The ortholog-specific behavior of these compounds suggest that a comparative pharmacology approach, using cross-ortholog chimeras, may be useful for identification of binding sites on human CFTR.

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15

Stenkiewicz-Witeska, Jan S., and Iuliana V. Ene. "Azole potentiation in Candida species." PLOS Pathogens 19, no. 8 (August 31, 2023): e1011583. http://dx.doi.org/10.1371/journal.ppat.1011583.

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Fungal infections are rising, with over 1.5 billion cases and more than 1 million deaths recorded each year. Among these, Candida infections are frequent in at-risk populations and the rapid development of drug resistance and tolerance contributes to their clinical persistence. Few antifungal drugs are available, and their efficacy is declining due to the environmental overuse and the expansion of multidrug-resistant species. One way to prolong their utility is by applying them in combination therapy. Here, we highlight recently described azole potentiators belonging to different categories: natural, repurposed, or novel compounds. We showcase examples of molecules and discuss their identified or proposed mode of action. We also emphasise the challenges in azole potentiator development, compounded by the lack of animal testing, the overreliance on Candida albicans and Candida auris, as well as the limited understanding of compound efficacy.

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16

Zhang, Song, Jun Wang, and Juhee Ahn. "Advances in the Discovery of Efflux Pump Inhibitors as Novel Potentiators to Control Antimicrobial-Resistant Pathogens." Antibiotics 12, no. 9 (September 7, 2023): 1417. http://dx.doi.org/10.3390/antibiotics12091417.

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The excessive use of antibiotics has led to the emergence of multidrug-resistant (MDR) pathogens in clinical settings and food-producing animals, posing significant challenges to clinical management and food control. Over the past few decades, the discovery of antimicrobials has slowed down, leading to a lack of treatment options for clinical infectious diseases and foodborne illnesses. Given the increasing prevalence of antibiotic resistance and the limited availability of effective antibiotics, the discovery of novel antibiotic potentiators may prove useful for the treatment of bacterial infections. The application of antibiotics combined with antibiotic potentiators has demonstrated successful outcomes in bench-scale experiments and clinical settings. For instance, the use of efflux pump inhibitors (EPIs) in combination with antibiotics showed effective inhibition of MDR pathogens. Thus, this review aims to enable the possibility of using novel EPIs as potential adjuvants to effectively control MDR pathogens. Specifically, it provides a comprehensive summary of the advances in novel EPI discovery and the underlying mechanisms that restore antimicrobial activity. In addition, we also characterize plant-derived EPIs as novel potentiators. This review provides insights into current challenges and potential strategies for future advancements in fighting antibiotic resistance.

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17

Alt, A., J. Witkin, and D. Bleakman. "AMPA Receptor Potentiators as Novel Antidepressants." Current Pharmaceutical Design 11, no. 12 (May 1, 2005): 1511–27. http://dx.doi.org/10.2174/1381612053764814.

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18

COOPER, RAYMOND, J. SCOTT WELLS та RICHARD B. SYKES. "NOVEL POTENTIATORS OF β-LACTAM ANTIBIOTICS". Journal of Antibiotics 38, № 4 (1985): 449–54. http://dx.doi.org/10.7164/antibiotics.38.449.

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19

Francotte, Pierre, Pascal de Tullio, Pierre Fraikin, Stephane Counerotte, Eric Goffin, and Bernard Pirotte. "In Search of Novel AMPA Potentiators." Recent Patents on CNS Drug Discovery 1, no. 3 (November 1, 2006): 239–46. http://dx.doi.org/10.2174/157488906778773661.

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20

LU, WEI, ISAO ADACHI, KENSAKU KANO, AKIKO YASUTA, KAZUO TORIIZUKA, MASAHARU UENO, and ISAMU HORIKOSHI. "Platelet aggregation potentiators from Cho-Rei." CHEMICAL & PHARMACEUTICAL BULLETIN 33, no. 11 (1985): 5083–87. http://dx.doi.org/10.1248/cpb.33.5083.

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21

Morel, Cécile, Frank R. Stermitz, George Tegos, and Kim Lewis. "Isoflavones As Potentiators of Antibacterial Activity." Journal of Agricultural and Food Chemistry 51, no. 19 (September 2003): 5677–79. http://dx.doi.org/10.1021/jf0302714.

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22

Cheng, H. M., and L. Chamley. "Cryptic natural autoantibodies and co-potentiators." Autoimmunity Reviews 7, no. 6 (June 2008): 431–34. http://dx.doi.org/10.1016/j.autrev.2008.03.011.

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23

Baust, John G., John Bischof, Andrew Gage, Anthony Robilotto, and John M. Baust. "012 Cryosensitization: Adjunctive potentiators for cryoablation." Cryobiology 67, no. 3 (December 2013): 401. http://dx.doi.org/10.1016/j.cryobiol.2013.09.018.

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24

Yeh, Han-I., Yoshiro Sohma, Katja Conrath, and Tzyh-Chang Hwang. "A common mechanism for CFTR potentiators." Journal of General Physiology 149, no. 12 (October 27, 2017): 1105–18. http://dx.doi.org/10.1085/jgp.201711886.

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Cystic fibrosis (CF) is a channelopathy caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a phosphorylation-activated and adenosine triphosphate (ATP)–gated chloride channel. In the past few years, high-throughput drug screening has successfully realized the first US Food and Drug Administration–approved therapy for CF, called ivacaftor (or VX-770). A more recent CFTR potentiator, GLPG1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide), has been shown to exhibit a higher efficacy than ivacaftor for the G551D mutation, yet the underlying mechanism of GLPG1837 remains unclear. Here we find that despite their differences in potency and efficacy, GLPG1837 and VX-770 potentiate CFTR gating in a remarkably similar manner. Specifically, they share similar effects on single-channel kinetics of wild-type CFTR. Their actions are independent of nucleotide-binding domain (NBD) dimerization and ATP hydrolysis, critical steps controlling CFTR’s gate opening and closing, respectively. By applying the two reagents together, we provide evidence that GLPG1837 and VX-770 likely compete for the same site, whereas GLPG1837 and the high-affinity ATP analogue 2′-deoxy-N6-(2-phenylethyl)-adenosine-5′-O-triphosphate (dPATP) work synergistically through two different sites. We also find that the apparent affinity for GLPG1837 is dependent on the open probability of the channel, suggesting a state-dependent binding of the drug to CFTR (higher binding affinity for the open state than the closed state), which is consistent with the classic mechanism for allosteric modulation. We propose a simple four-state kinetic model featuring an energetic coupling between CFTR gating and potentiator binding to explain our experimental results.

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Stein, Marco, Simon J. Middendorp, Valentina Carta, Ervin Pejo, Douglas E. Raines, Stuart A. Forman, Erwin Sigel, and Dirk Trauner. "Azo-Propofols: Photochromic Potentiators of GABAAReceptors." Angewandte Chemie 124, no. 42 (September 11, 2012): 10652–56. http://dx.doi.org/10.1002/ange.201205475.

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Stein, Marco, Simon J. Middendorp, Valentina Carta, Ervin Pejo, Douglas E. Raines, Stuart A. Forman, Erwin Sigel, and Dirk Trauner. "Azo-Propofols: Photochromic Potentiators of GABAAReceptors." Angewandte Chemie International Edition 51, no. 42 (September 11, 2012): 10500–10504. http://dx.doi.org/10.1002/anie.201205475.

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Jih, Kang-Yang, Wen-Ying Lin, Yoshiro Sohma, and Tzyh-Chang Hwang. "CFTR potentiators: from bench to bedside." Current Opinion in Pharmacology 34 (June 2017): 98–104. http://dx.doi.org/10.1016/j.coph.2017.09.015.

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Schrank, Cassandra L., Ingrid K. Wilt, Carlos Monteagudo Ortiz, Brittney A. Haney, and William M. Wuest. "Using membrane perturbing small molecules to target chronic persistent infections." RSC Medicinal Chemistry 12, no. 8 (2021): 1312–24. http://dx.doi.org/10.1039/d1md00151e.

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Kerr, Colm, David Morrissy, Mary Horgan, and Barry J. Plant. "Microbial clues lead to a diagnosis of cystic fibrosis in late adulthood." BMJ Case Reports 13, no. 4 (April 2020): e233470. http://dx.doi.org/10.1136/bcr-2019-233470.

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Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder among Caucasian populations. The majority of CF cases are diagnosed in childhood; however, increasing numbers of adults are being diagnosed with the condition. We present the case of a 65-year-old Irish woman presenting with a chronic cough and a history of recurrent respiratory tract infections. Staphylococcus aureus, Scedosporium apiospermum and Stenotrophomonas maltophilia were grown from bronchoalveolar lavage raising suspicion for CF. Sweat testing was negative; however, genetic testing revealed the presence of ∆F508 and R117H CF mutations, the latter mutation conferring a milder form of CF. The patient commenced treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator medication ivacaftor to good effect. Novel CFTR potentiators and modulators have significant potential to benefit morbidity and mortality in this group. In this case, the microbiological results were key in pursuing genetic testing and diagnosing CF.

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Phuan, Puay-Wah, Jung-Ho Son, Joseph-Anthony Tan, Clarabella Li, Ilaria Musante, Lorna Zlock, Dennis W. Nielson, et al. "Combination potentiator (‘co-potentiator’) therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators." Journal of Cystic Fibrosis 17, no. 5 (September 2018): 595–606. http://dx.doi.org/10.1016/j.jcf.2018.05.010.

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Bose, Samuel J., Marcel J. C. Bijvelds, Yiting Wang, Jia Liu, Zhiwei Cai, Alice G. M. Bot, Hugo R. de Jonge, and David N. Sheppard. "Differential thermostability and response to cystic fibrosis transmembrane conductance regulator potentiators of human and mouse F508del-CFTR." American Journal of Physiology-Lung Cellular and Molecular Physiology 317, no. 1 (July 1, 2019): L71—L86. http://dx.doi.org/10.1152/ajplung.00034.2019.

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Cross-species comparative studies have highlighted differences between human and mouse cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial Cl− channel defective in cystic fibrosis (CF). Here, we compare the impact of the most common CF mutation F508del on the function of human and mouse CFTR heterologously expressed in mammalian cells and their response to CFTR modulators using the iodide efflux and patch-clamp techniques. Once delivered to the plasma membrane, human F508del-CFTR exhibited a severe gating defect characterized by infrequent channel openings and was thermally unstable, deactivating within minutes at 37°C. By contrast, the F508del mutation was without effect on the gating pattern of mouse CFTR, and channel activity demonstrated thermostability at 37°C. Strikingly, at all concentrations tested, the clinically approved CFTR potentiator ivacaftor was without effect on the mouse F508del-CFTR Cl− channel. Moreover, eight CFTR potentiators, including ivacaftor, failed to generate CFTR-mediated iodide efflux from CHO cells expressing mouse F508del-CFTR. However, they all produced CFTR-mediated iodide efflux with human F508del-CFTR-expressing CHO cells, while fifteen CFTR correctors rescued the plasma membrane expression of both human and mouse F508del-CFTR. Interestingly, the CFTR potentiator genistein enhanced CFTR-mediated iodide efflux from CHO cells expressing either human or mouse F508del-CFTR, whereas it only potentiated human F508del-CFTR Cl− channels in cell-free membrane patches, suggesting that its action on mouse F508del-CFTR is indirect. Thus, the F508del mutation has distinct effects on human and mouse CFTR Cl− channels.

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Ribeiro, Carla M. P., and Martina Gentzsch. "Impact of Airway Inflammation on the Efficacy of CFTR Modulators." Cells 10, no. 11 (November 22, 2021): 3260. http://dx.doi.org/10.3390/cells10113260.

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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.

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Liu, Fangyu, Zhe Zhang, Anat Levit, Jesper Levring, Kouki K. Touhara, Brian K. Shoichet, and Jue Chen. "Structural identification of a hotspot on CFTR for potentiation." Science 364, no. 6446 (June 20, 2019): 1184–88. http://dx.doi.org/10.1126/science.aaw7611.

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Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo–electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)–approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.

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Rowe, S. M., and A. S. Verkman. "Cystic Fibrosis Transmembrane Regulator Correctors and Potentiators." Cold Spring Harbor Perspectives in Medicine 3, no. 7 (July 1, 2013): a009761. http://dx.doi.org/10.1101/cshperspect.a009761.

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Ensinck, Marjolein M., Liesbeth De Keersmaecker, Anabela S. Ramalho, Senne Cuyx, Stephanie Van Biervliet, Lieven Dupont, Frauke Christ, Zeger Debyser, François Vermeulen, and Marianne S. Carlon. "Novel CFTR modulator combinations maximise rescue of G85E and N1303K in rectal organoids." ERJ Open Research 8, no. 2 (February 11, 2022): 00716–2021. http://dx.doi.org/10.1183/23120541.00716-2021.

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IntroductionCystic fibrosis (CF) is a severe monogenic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Several types of CFTR modulators (correctors/potentiators) have been developed to overcome protein dysfunction associated with these mutations. CFTR modulator therapy is now available for the major CF-causing mutations; however, 10% of people with CF remain without causal treatments. By combining investigational and market-approved CFTR modulators, we aimed to maximise functional rescue of iva-, luma- and tezacaftor refractory mutants G85E and N1303K.MethodsWe used the well-established forskolin-induced swelling (FIS) in primary rectal organoids to assess responses to different CFTR corrector and potentiator types. The FIS analysis was performed with brightfield microscopy, allowing both 1-h and 24-h follow-up. Corrector and potentiator activity of elexacaftor was investigated.ResultsFor G85E, maximal rescue was observed by a combination of elexacaftor and corr4a. For N1303K, the quadruple combination teza-elexa-ivacaftor with apigenin was required to obtain a rescue similar to that of luma-ivacaftor rescued F508del. Elexacaftor rescued G85E and N1303K by different mechanisms, with chronic corrector effects on G85E and acute potentiation of N1303K only in the presence of ivacaftor. Synergy in N1303K rescue for iva-elexacaftor and apigenin suggests at least three potentiator mechanisms for this mutant. 24-h FIS identified ivacaftor as the main CFTR modulator for N1303K and elexacaftor and apigenin as co-potentiators.ConclusionsNovel combinations of CFTR modulators can further improve functional rescue of G85E and N1303K in rectal organoids, although for N1303K, more effective CFTR modulators are still needed.

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Abd El-sattar, Nour E. A., Eman H. K. Badawy, Eman Z. Elrazaz, and Nasser S. M. Ismail. "Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design, synthesis and antitumor activity." RSC Advances 11, no. 8 (2021): 4454–64. http://dx.doi.org/10.1039/d0ra10321g.

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PARP-1 are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death.

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37

Sinha, Sheetal, Vidhya Bharathi Dhanabal, Veronica Lavanya Manivannen, Floriana Cappiello, Suet-Mien Tan та Surajit Bhattacharjya. "Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing". International Journal of Molecular Sciences 24, № 1 (23 грудня 2022): 263. http://dx.doi.org/10.3390/ijms24010263.

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Many antibiotics are ineffective in killing Gram-negative bacteria due to the permeability barrier of the outer-membrane LPS. Infections caused by multi-drug-resistant Gram-negative pathogens require new antibiotics, which are often difficult to develop. Antibiotic potentiators disrupt outer-membrane LPS and can assist the entry of large-scaffold antibiotics to the bacterial targets. In this work, we designed a backbone-cyclized ultra-short, six-amino-acid-long (WKRKRY) peptide, termed cWY6 from LPS binding motif of β-boomerang bactericidal peptides. The cWY6 peptide does not exhibit any antimicrobial activity; however, it is able to permeabilize the LPS outer membrane. Our results demonstrate the antibiotic potentiator activity in the designed cWY6 peptide for several conventional antibiotics (vancomycin, rifampicin, erythromycin, novobiocin and azithromycin). Remarkably, the short cWY6 peptide exhibits wound-healing activity in in vitro assays. NMR, computational docking and biophysical studies describe the atomic-resolution structure of the peptide in complex with LPS and mode of action in disrupting the outer membrane. The dual activities of cWY6 peptide hold high promise for further translation to therapeutics.

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Tomita, S., M. Sekiguchi, K. Wada, R. A. Nicoll, and D. S. Bredt. "Stargazin controls the pharmacology of AMPA receptor potentiators." Proceedings of the National Academy of Sciences 103, no. 26 (June 19, 2006): 10064–67. http://dx.doi.org/10.1073/pnas.0603128103.

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Vermote, Arno, and Serge Van Calenbergh. "Small-Molecule Potentiators for Conventional Antibiotics againstStaphylococcus aureus." ACS Infectious Diseases 3, no. 11 (October 4, 2017): 780–96. http://dx.doi.org/10.1021/acsinfecdis.7b00084.

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Thorarensen, Atli, Alice L. Presley-Bodnar, Keith R. Marotti, Timothy P. Boyle, Charlotte L. Heckaman, Michael J. Bohanon, Paul K. Tomich, Gary E. Zurenko, Michael T. Sweeney, and Betty H. Yagi. "3-Arylpiperidines as potentiators of existing antibacterial agents." Bioorganic & Medicinal Chemistry Letters 11, no. 14 (July 2001): 1903–6. http://dx.doi.org/10.1016/s0960-894x(01)00330-4.

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Clancy, J. P. "CFTR Potentiators: Not an Open and Shut Case." Science Translational Medicine 6, no. 246 (July 23, 2014): 246fs27. http://dx.doi.org/10.1126/scitranslmed.3009674.

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42

Fox, Jeffrey L. "Candidate Antimicrobials, Enhancers, Potentiators, Combos Plus New Probe." Microbe Magazine 11, no. 9 (September 1, 2016): 375–77. http://dx.doi.org/10.1128/microbe.11.375.1.

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Solomon, George M., Susan G. Marshall, Bonnie W. Ramsey, and Steven M. Rowe. "Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors." Pediatric Pulmonology 50, S40 (June 19, 2015): S3—S13. http://dx.doi.org/10.1002/ppul.23240.

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Voronkova, A. Yu, N. V. N.V.Bulatenko, Yu L. Yu.L.Melyanovskaya, A. S. A.S.Efremova, T. B. T.B.Bukharova, S. I. S.I.Kutsev, H. R. H.R. de Jonge, N. V. N.V.Petrova, and D. V. D.V.Goldshtein. "Selection of CFTR modulators for children with the W1282R variant." Voprosy praktičeskoj pediatrii 17, no. 3 (2022): 83–91. http://dx.doi.org/10.20953/1817-7646-2022-3-83-91.

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Objective. To study the clinical manifestations of W1282R variant, functional activity of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, and effectiveness of CFTR modulator therapy in patients with the W1282R variant. Materials and methods included medical records, intestinal current measurement method (ICM) and method of intestinal organoids (IO). Results. The c.3844T>C (p.Trp1282Arg, W1282R) variant refers to missense mutations. The Cystic Fibrosis (CF) Patient Registry of the Russian Federation (2019) provides the data on 34 patients with the W1282R variant in the genotype. Clinical manifestations in two patients with the W1282R variant corresponds to the severe course of CF. ICM method revealed the loss of CFTR function. The effect of VX-809 corrector, VX-770 potentiator and their combined use were assessed in each patient using the method of IO. Conclusion. The results indicated a “severe” W1282R variant. The application of VX-809 corrector had no effect on the restoration of chloride channel function, unlike the F508del homozygous control sample (class II mutations). The VX-770 potentiator had no effect on the kinetic properties of CFTR protein. But in both patients, a significant restoration of lost channel function (~45%) was recorded with the combined use of VX-809 corrector and VX-770 potentiator, which is typical for class III and class IV variants. This challenges the conclusions that the W1282R variant has class II characteristics only. Combination therapy with VX-809 and VX-770 may be recommended for patients with the W1282R/CFTRdel2,3 and W1282R/F508del genotypes. Key words: cystic fibrosis, CFTR gene, W1282R pathogenic variant, intestinal current measurement method, intestinal organoids, forskolin-induced swelling assay, correctors, potentiators, target therapy, ivacaftor, lumacaftor

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Mitash, Nilay, Fangping Mu, Joshua E. Donovan, Michael M. Myerburg, Sarangarajan Ranganathan, Catherine M. Greene та Agnieszka Swiatecka-Urban. "Transforming Growth Factor-β1 Selectively Recruits microRNAs to the RNA-Induced Silencing Complex and Degrades CFTR mRNA under Permissive Conditions in Human Bronchial Epithelial Cells". International Journal of Molecular Sciences 20, № 19 (5 жовтня 2019): 4933. http://dx.doi.org/10.3390/ijms20194933.

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<p>Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (<italic>CFTR</italic>) gene lead to cystic fibrosis (CF). The most common mutation F508del inhibits folding and processing of CFTR protein. FDA-approved correctors rescue the biosynthetic processing of F508del-CFTR protein, while potentiators improve the rescued CFTR channel function. Transforming growth factor (TGF-β1), overexpressed in many CF patients, blocks corrector/potentiator rescue by inhibiting CFTR mRNA in vitro. Increased TGF-β1 signaling and acquired CFTR dysfunction are present in other lung diseases. To study the mechanism of TGF-β1 repression of CFTR, we used molecular, biochemical, and functional approaches in primary human bronchial epithelial cells from over 50 donors. TGF-β1 destabilized CFTR mRNA in cells from lungs with chronic disease, including CF, and impaired F508del-CFTR rescue by new-generation correctors. TGF-β1 increased the active pool of selected micro(mi)RNAs validated as CFTR inhibitors, recruiting them to the RNA-induced silencing complex (RISC). Expression of F508del-CFTR globally modulated TGF-β1-induced changes in the miRNA landscape, creating a permissive environment required for degradation of F508del-CFTR mRNA. In conclusion, TGF-β1 may impede the full benefit of corrector/potentiator therapy in CF patients. Studying miRNA recruitment to RISC under disease-specific conditions may help to better characterize the miRNAs utilized by TGF-β1 to destabilize CFTR mRNA.

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Csanády, László, and Beáta Töröcsik. "Structure–activity analysis of a CFTR channel potentiator: Distinct molecular parts underlie dual gating effects." Journal of General Physiology 144, no. 4 (September 29, 2014): 321–36. http://dx.doi.org/10.1085/jgp.201411246.

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The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette transporter superfamily that functions as an epithelial chloride channel. Gating of the CFTR ion conduction pore involves a conserved irreversible cyclic mechanism driven by ATP binding and hydrolysis at two cytosolic nucleotide-binding domains (NBDs): formation of an intramolecular NBD dimer that occludes two ATP molecules opens the pore, whereas dimer disruption after ATP hydrolysis closes it. CFTR dysfunction resulting from inherited mutations causes CF. The most common CF mutation, deletion of phenylalanine 508 (ΔF508), impairs both protein folding and processing and channel gating. Development of ΔF508 CFTR correctors (to increase cell surface expression) and potentiators (to enhance open probability, Po) is therefore a key focus of CF research. The practical utility of 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB), one of the most efficacious potentiators of ΔF508 CFTR identified to date, is limited by its pore-blocking side effect. NPPB-mediated stimulation of Po is unique in that it involves modulation of gating transition state stability. Although stabilization by NPPB of the transition state for pore opening enhances both the rate of channel opening and the very slow rate of nonhydrolytic closure, because of CFTR’s cyclic gating mechanism, the net effect is Po stimulation. In addition, slowing of ATP hydrolysis by NPPB delays pore closure, further enhancing Po. Here we show that NPPB stimulates gating at a site outside the pore and that these individual actions of NPPB on CFTR are fully attributable to one or the other of its two complementary molecular parts, 3-nitrobenzoate (3NB) and 3-phenylpropylamine (3PP), both of which stimulate Po: the pore-blocking 3NB selectively stabilizes the transition state for opening, whereas the nonblocking 3PP selectively slows the ATP hydrolysis step. Understanding structure–activity relationships of NPPB might prove useful for designing potent, clinically relevant CFTR potentiators.

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Pinkerton, Anthony B., Rowena V. Cube, John H. Hutchinson, Joyce K. James, Michael F. Gardner, Hervé Schaffhauser, Blake A. Rowe, Lorrie P. Daggett, and Jean-Michel Vernier. "Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-Thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators." Bioorganic & Medicinal Chemistry Letters 14, no. 23 (December 2004): 5867–72. http://dx.doi.org/10.1016/j.bmcl.2004.09.028.

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48

Pinkerton, Anthony B., Rowena V. Cube, John H. Hutchinson, Joyce K. James, Michael F. Gardner, Blake A. Rowe, Hervé Schaffhauser, et al. "Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 3: Identification and biological activity of indanone containing mGlu2 receptor potentiators." Bioorganic & Medicinal Chemistry Letters 15, no. 6 (March 2005): 1565–71. http://dx.doi.org/10.1016/j.bmcl.2005.01.077.

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49

Si, Yaru, Kang Ma, Yingfeng Hu, Hongzong Si, and Honglin Zhai. "QSAR Model Study of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole of Cystic- brosis-transmembrane Conductance-regulator Gene Potentiators." Letters in Drug Design & Discovery 19, no. 4 (April 2022): 269–78. http://dx.doi.org/10.2174/1570180818666211022142920.

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Background: Cystic fibrosis (CF) is a genetic disease, which has no effective treatment. Objective: The aim of this study is to predict the EC50 value of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole core as a novel chemotype of potentiators to establish a highly predicting quantitative structure-activity relationship model. Methods: 41 products were optimized, and a linear model was built by a heuristic method in CODESSA program. In this study, 3 descriptors were selected and utilized to build a nonlinear model in gene expression programming. Results: The square of the correlation coefficient of the heuristic method is 0.57, and the s2 is 0.30. In gene expression programming, the square of correlation coefficient and the mean square error for the training set are 0.74 and 0.13, respectively. The square of correlation coefficient and the mean square error for the test set are 0.70 and 0.27, respectively. Conclusion: The GEP model has stronger predictive ability to help develop the novel structure of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole of cystic-brosis-transmembrane conductance-regulator gene potentiators.

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Kassab, Amal, Nasser Rizk, and Satya Prakash. "The Role of Systemic Filtrating Organs in Aging and Their Potential in Rejuvenation Strategies." International Journal of Molecular Sciences 23, no. 8 (April 14, 2022): 4338. http://dx.doi.org/10.3390/ijms23084338.

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Advances in aging studies brought about by heterochronic parabiosis suggest that agingmight be a reversable process that is affected by changes in the systemic milieu of organs andcells. Given the broadness of such a systemic approach, research to date has mainly questioned theinvolvement of “shared organs” versus “circulating factors”. However, in the absence of a clearunderstanding of the chronological development of aging and a unified platform to evaluate thesuccesses claimed by specific rejuvenation methods, current literature on this topic remains scattered.Herein, aging is assessed from an engineering standpoint to isolate possible aging potentiators via ajuxtaposition between biological and mechanical systems. Such a simplification provides a generalframework for future research in the field and examines the involvement of various factors in aging.Based on this simplified overview, the kidney as a filtration organ is clearly implicated, for the firsttime, with the aging phenomenon, necessitating a re-evaluation of current rejuvenation studies tountangle the extent of its involvement and its possible role as a potentiator in aging. Based on thesefindings, the review concludes with potential translatable and long-term therapeutics for aging whileoffering a critical view of rejuvenation methods proposed to date.

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