Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria

Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (UROIIISP248Q/P248Q). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases.

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The Pharmacological Chaperone AT2220 Increases the Specific Activity and Lysosomal Delivery of Mutant Acid Alpha-Glucosidase, and Promotes Glycogen Reduction in a Transgenic Mouse Model of Pompe Disease

PLoS ONE ◽

10.1371/journal.pone.0102092 ◽

2014 ◽

Vol 9 (7) ◽

pp. e102092 ◽

Cited By ~ 17

Author(s):

Richie Khanna ◽

Allan C. Powe ◽

Yi Lun ◽

Rebecca Soska ◽

Jessie Feng ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Pompe Disease ◽

Specific Activity ◽

Transgenic Mouse Model ◽

Pharmacological Chaperone ◽

Alpha Glucosidase

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The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models

Biomolecules ◽

10.3390/biom11121856 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1856

Author(s):

Pedro Besada ◽

María Gallardo-Gómez ◽

Tania Pérez-Márquez ◽

Lucía Patiño-Álvarez ◽

Sergio Pantano ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Pharmacological Chaperone ◽

Pharmacological Chaperones ◽

Enzyme Replacement ◽

Cellular Models ◽

Activity Measurements ◽

Progressive Accumulation ◽

Potential Use

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.

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Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Nutrients ◽

10.3390/nu13041181 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1181

Author(s):

Raffaella Soleti ◽

Marine Coué ◽

Charlotte Trenteseaux ◽

Gregory Hilairet ◽

Lionel Fizanne ◽

...

Keyword(s):

Blood Pressure ◽

Mouse Model ◽

Aortic Root ◽

De Novo ◽

Body Weight Gain ◽

Density Lipoprotein ◽

De Novo Lipogenesis ◽

Hemodynamic Parameters ◽

Cellular Models ◽

Genetic Mouse Model

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

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Co-Purification of Recombinant Modified Glucagon-Like and Glucose-Dependent Insulinotropic Peptide to Create a Two-Component Drug for the Treatment of Type 2 Diabetes Mellitus and Obesity

Biotekhnologiya ◽

10.21519/0234-2758-2021-37-6-74-83 ◽

2021 ◽

Vol 37 (6) ◽

pp. 74-83

Author(s):

A.Yu. Gorbunova ◽

E.P. Sannikova ◽

I.I. Gubaidullin ◽

O.M. Ignatova ◽

M.Yu. Kopaeva ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Mouse Model ◽

Specific Activity ◽

Two Component ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Insulinotropic Peptide

In addition to the previously developed recombinant modified human glucagon-like peptide 1 (rmglp1, Glypin), a recombinant modified human glucose-dependent insulinotropic peptide (RMGIP) has been obtained. A new universal reverse-phase HPLC technique has been proposed allowing quantitative analysis of rmGlp1 and rmGip separately and as part of a two-component preparation. The data show that the design of recombinant human rmGip according to the Glypine formula makes it possible to produce one-component and two-component preparations containing various rmGip and rmGlp1 protein ratios ranging from 1:0 to 20:1, using cell biomass samples mixed in predetermined proportions. Studies of human rmGip activity in a mouse model revealed reduced specific activity and signs of weak antagonistic effects. In this regard, there is a need for further study of human rmGip activity in a mouse model, including the use of alternative mouse or rat rmGip. type 2 diabetes mellitus; two-component drug, glucose-dependent insulinotropic peptide, glucagon-like peptide-1 The work was supported by the Internal Grant from National Research Center Kurchatov Institute.

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Natural and pharmacological chaperones against accelerated protein degradation: uroporphyrinogen III synthase and congenital erythropoietic porphyria

Protein Homeostasis Diseases ◽

10.1016/b978-0-12-819132-3.00018-x ◽

2020 ◽

pp. 389-413

Author(s):

Ganeko Bernardo-Seisdedos ◽

David Gil ◽

Jean-Marc Blouin ◽

Emmanuel Richard ◽

Oscar Millet

Keyword(s):

Protein Degradation ◽

Pharmacological Chaperones ◽

Congenital Erythropoietic Porphyria

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A knock-in mouse model of congenital erythropoietic porphyria

Genomics ◽

10.1016/j.ygeno.2005.08.018 ◽

2006 ◽

Vol 87 (1) ◽

pp. 84-92 ◽

Cited By ~ 19

Author(s):

C. Ged ◽

M. Mendez ◽

E. Robert ◽

M. Lalanne ◽

I. Lamrissi-Garcia ◽

...

Keyword(s):

Mouse Model ◽

Congenital Erythropoietic Porphyria

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Distinct proteostasis states drive pharmacologic chaperone susceptibility for Cystic Fibrosis Transmembrane Conductance Regulator misfolding mutants

10.1101/2021.09.09.459524 ◽

2021 ◽

Author(s):

Eli Fritz McDonald ◽

Carleen Mae P. Sabusap ◽

Minsoo Kim ◽

Lars Plate

Keyword(s):

Cystic Fibrosis ◽

Protein Misfolding ◽

Clinical Success ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Pharmacological Chaperone ◽

Pharmacological Chaperones ◽

Misfolding Diseases ◽

The Impact ◽

Cystic Fibrosis Transmembrane

ABSTRACTPharmacological chaperones represent a class of therapeutic compounds for treating protein misfolding diseases. One of the most prominent examples is the FDA-approved pharmacological chaperone lumacaftor (VX-809), which has transformed cystic fibrosis (CF) therapy. CF is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). VX-809 corrects folding of F508del CFTR, the most common patient mutation, yet F508del exhibits only mild VX-809 response. In contrast, rarer mutations P67L and L206W are hyper-responsive to VX-809, while G85E is non-responsive. Despite the clinical success of VX-809, the mechanistic origin for the distinct susceptibility of mutants remains unclear. Here, we use interactomics to characterize the impact of VX-809 on proteostasis interactions of P67L and L206W and compare these to F508del and G85E. We determine hyper-responsive mutations P67L and L206W exhibit decreased interactions with proteasomal, and autophagy degradation machinery compared to F508del and G85E. We then show inhibiting the proteasome attenuates P67L and L206W VX-809 response, and inhibiting the lysosome attenuates F508del VX-809 response. Our data suggests a previously unidentified but required role for protein degradation in VX-809 correction. Furthermore, we present an approach for identifying proteostasis characteristics of mutant-specific therapeutic response to pharmacological chaperones.

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Second-Generation Pharmacological Chaperones: Beyond Inhibitors

Molecules ◽

10.3390/molecules25143145 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3145 ◽

Cited By ~ 1

Author(s):

My Lan Tran ◽

Yves Génisson ◽

Stéphanie Ballereau ◽

Cécile Dehoux

Keyword(s):

Protein Misfolding ◽

First Generation ◽

Second Generation ◽

Missense Mutations ◽

Loss Of Function ◽

Pharmacological Chaperone ◽

Conformational Diseases ◽

Pharmacological Chaperones ◽

Drug Candidates ◽

Binding Pockets

Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

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The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse AD Models

Cells ◽

10.3390/cells9051204 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1204

Author(s):

Anaïs Bécot ◽

Raphaëlle Pardossi-Piquard ◽

Alexandre Bourgeois ◽

Eric Duplan ◽

Qingli Xiao ◽

...

Keyword(s):

Transcription Factor ◽

Mouse Model ◽

Early Stage ◽

Amyloid Β ◽

Newborn Mice ◽

Cellular Models ◽

In Vivo Experiments ◽

Lysosome Biogenesis ◽

Transcription Factor Eb

: Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

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