Review
Chemistry, Medicinal
Macarena Martinez-Bailen, Francesca Clemente, Camilla Matassini, Francesca Cardona
Summary: Pharmaceutical chaperones (PCs) are small compounds that can bind and stabilize misfolded proteins, helping them regain their native conformation and biological activity. They are especially beneficial in treating lysosomal storage disorders (LSDs) caused by genetic mutations. However, despite the importance of the GCase enzyme in treating LSDs and neurological disorders, no PC for this enzyme has been approved for market use. This review highlights the efforts made in the past 7 years to identify new PCs for the GCase enzyme, with a focus on glycomimetic-based compounds.
Article
Biochemistry & Molecular Biology
Costanza Vanni, Francesca Clemente, Paolo Paoli, Amelia Morrone, Camilla Matassini, Andrea Goti, Francesca Cardona
Summary: The synthesis of five new multivalent derivatives of a trihydroxypiperidine iminosugar was achieved through copper catalyzed alkyne-azide cycloaddition. These multivalent compounds showed much more potent inhibitory effects on lysosomal GCase, with the trivalent derivative demonstrating a 2-fold recovery of enzyme activity on Gaucher patient fibroblasts. Furthermore, thermal denaturation experiments indicated its ability to enhance stability of the recombinant enzyme used in therapy.
Article
Chemistry, Multidisciplinary
Andres G. Santana, Kyle Robinson, Chelsea Vickers, Matthew C. Deen, Hong-Ming Chen, Stephen Zhou, Ben Dai, Maria Fuller, Alisdair B. Boraston, David J. Vocadlo, Lorne A. Clarke, Stephen G. Withers
Summary: In this study, we synthesized a novel pharmacological chaperone that improves the low enzyme activity in Gaucher disease patients. Cell and animal experiments demonstrated the effectiveness of this chaperone in enhancing enzymatic activity, suggesting its potential therapeutic value.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Clinical Neurology
A. E. Kopytova, G. N. Rychkov, M. A. Nikolaev, G. Baydakova, A. A. Cheblokov, K. A. Senkevich, D. A. Bogdanova, O. Bolshakova, I. Miliukhina, V. A. Bezrukikh, G. N. Salogub, S. Sarantseva, T. C. Usenko, E. Y. Zakharova, A. K. Emelyanov, S. N. Pchelina
Summary: Treatment with ambroxol significantly increased GCase activity and reduced HexSph concentration in GD and GBA-PD patients, as well as promoted GCase translocation to lysosomes. GD macrophage treatment demonstrated increased GCase levels and colocalization with the lysosomal marker LAMP2. Molecular docking and dynamics simulations revealed potential binding modes of ambroxol to mutant GCase, showing promising therapeutic potential for GD and GBA-PD patients.
PARKINSONISM & RELATED DISORDERS
(2021)
Article
Biochemistry & Molecular Biology
Tereza Cristina Santos Evangelista, Oscar Lopez, Adrian Puerta, Miguel X. Fernandes, Sabrina Baptista Ferreira, Jose M. Padron, Jose G. Fernandez-Bolanos, Magne O. Sydnes, Emil Lindback
Summary: The synthesis of four heterodimers connecting a 1-deoxynojirimycin moiety with a benzotriazole scaffold using the copper(I)-catalysed azide-alkyne cycloaddition was reported. These heterodimers showed preferential inhibition against butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE) in the micromolar concentration range. The most potent inhibitor of BuChE demonstrated a mixed inhibition mode, with the benzotriazole and 1-deoxynojirimycin moiety accommodated in the catalytic anionic site and peripheral anionic site of AChE, respectively. However, the binding mode to BuChE was different, with the benzotriazole moiety accommodated in the catalytic anionic site.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Review
Clinical Neurology
Daniel Ysselstein, Tiffany J. Young, Maria Nguyen, Shalini Padmanabhan, Warren D. Hirst, Nicolas Dzamko, Dimitri Krainc
Summary: Mutations in the GBA1 gene, which encodes the GCase protein, are a common genetic risk factor for Parkinson's disease and dementia. The loss of GCase activity is associated with the onset of various diseases. Inconsistencies in measuring GCase enzymatic activity could hinder the development of GCase-targeted therapies.
MOVEMENT DISORDERS
(2021)
Article
Clinical Neurology
Nurit Omer, Nir Giladi, Tanya Gurevich, Anat Bar-Shira, Mali Gana-Weisz, Tal Glinka, Orly Goldstein, Meir Kestenbaum, Jesse M. Cedarbaum, Omar S. Mabrouk, Kyle B. Fraser, Julia C. Shirvan, Avi Orr-Urtreger, Anat Mirelman, Avner Thaler
Summary: This study investigated the association between GCase activity, PD phenotype, and prodromal PD probability in carriers of GBA gene mutations, finding that low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort.
MOVEMENT DISORDERS
(2022)
Article
Chemistry, Organic
Yi-Xian Li, Jun-Zhe Wang, Yuna Shimadate, Maki Kise, Atsushi Kato, Yue-Mei Jia, George W. J. Fleet, Chu-Yi Yu
Summary: The C-7 fluorinated derivatives of casuarine and australine, important polyhydroxylated pyrrolizidines, were successfully synthesized using organocatalytic stereoselective alpha-fluorination of aldehydes as a key step. This strategy can also be applied to the synthesis of challenging fluorinated iminosugars and carbohydrates. Docking studies revealed that the potent inhibitions of trehalase and amyloglucosidase by the fluorinated polyhydroxylated pyrrolizidines are mainly due to the interaction of fluorine atoms in these iminosugars with the amino acid residues of the corresponding enzymes. Additionally, unusual anion-pi interactions were established between the C-7 fluoride and a hydrophobic pocket in amyloglucosidase. These unexpected docking modes and structure-activity relationship studies highlight the significance of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Jilai Wu, Lulu Su, Tongguan Jia, Xiaoming Xu, Yaxin Cui, Chao Wei, Xiaoliu Li, Hua Chen
Summary: A simple and efficient one-pot synthesis method has been developed for the stereoselective synthesis of novel fused multicyclic iminosugars with structural diversity, using an aza-Diels-Alder mechanism. The adaptability of this method has been demonstrated by using a variety of aromatic amines and tosylated sugars.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Biochemistry & Molecular Biology
Martina De Angelis, Ludovica Primitivo, Federica Lizzio, Sonia Agostinelli, Carla Sappino, Ilaria Ben Romdan, Luciano Bonanni, Andrea D'Annibale, Roberto Antonioletti, Alessandra Ricelli, Giuliana Righi
Summary: In this study, we have described a versatile approach for synthesizing the pyrrolizidine alkaloids skeleton by modifying our original strategy used for pyrrolidine iminosugars synthesis. The key steps involve the regio- and stereoselective azidolysis of a suitable chiral vinyl epoxide and the asymmetric dihydmxylation of the corresponding azido alcohol. The synthesized iminosugars possess complete stereocontrol and hold significant importance due to their wide range of biological properties.
CARBOHYDRATE RESEARCH
(2022)
Article
Chemistry, Medicinal
Tamaki Hoshikawa, Toru Watanabe, Makoto Kotake, Nathalie Tiberghien, Chi -kit Woo, Sian Lewis, Thomas Briston, Mumta Koglin, James M. Staddon, Ben Powney, Anthony H. V. Schapira, Andrew K. Takle
Summary: Glucocerebrosidase (GCase) is an enzyme encoded by the GBA1 gene, and its loss of function variants cause Gaucher disease (GD). Heterozygous variants of GBA1 are also the strongest common genetic risk factor for Parkinson's disease (PD). A compound with sub-micromolar activity was identified as a GCase pharmacological chaperone, and it was further optimized to a novel compound with improved ADME and physicochemical properties for investigating GCase pharmacology.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Ren-Feng Li, Jian-Xing Yang, Jing Liu, Guo-Min Ai, Hui-Yan Zhang, Li-Yue Xu, Si-Bing Chen, Hong-Xin Zhang, Xiao-Liu Li, Zhi-Ran Cao, Ke-Rang Wang
Summary: The paper synthesized two positional isomeric perylene bisimide derivatives and studied their performance in glycosidase inhibition and hypoglycemic effects. PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice, with the highest binding and hydrogen bond energy related to the isomeric effect on hypoglycemic activity. This work introduced a new approach to develop antihyperglycemic agents in the field of multivalent glycomimetics.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Makaila L. Furderer, Ellen Hertz, Grisel J. Lopez, Ellen Sidransky
Summary: Deficiency of acid beta-glucocerebrosidase activity due to mutations in GBA1 causes Gaucher disease (GD). GD patients exhibit a wide range of symptoms, from asymptomatic adults to severe neurodegeneration. GBA1 variants are also important risk factors for several common Lewy body disorders (LBDs). Further neuropathological examinations in GD are needed to understand disease-specific patterns and mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Georg Niggemeyer, Anastasia Knyazeva, Raphael Gasper, Dale Corkery, Pia Bodenbinder, Julian J. Holstein, Sonja Sievers, Yao-Wen Wu, Herbert Waldmann
Summary: Design and synthesis of pseudo-natural products through recombination of natural product fragments enables the discovery of novel biologically relevant chemical matter. In this study, the combination of this principle with macrocycle formation was described, leading to the efficient synthesis of 163 macrocyclic pseudo-natural products. Biological investigation revealed their potent inducers of autophagy-related processes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Cell Biology
Ali Esfandiary, David Isaac Finkelstein, Nicolas Hans Voelcker, David Rudd
Summary: Alterations in sphingolipid metabolism may serve as potential diagnostic features for Parkinson's Disease (PD), particularly for idiopathic PD (iPD). The prodromal stage of iPD, characterized by non-specific symptoms, can occur up to 20 years before motor function loss. By studying the changes in sphingolipid metabolism, biomarkers for early-stage diagnosis of iPD can potentially be identified.
Article
Chemistry, Medicinal
Marcello Casertano, Massimo Genovese, Paolo Paoli, Alice Santi, Anna Aiello, Marialuisa Menna, Concetta Imperatore
Summary: The chemical investigation of Clavelina lepadiformis, a Mediterranean ascidian, led to the discovery of a new compound named lepadin L, along with two known metabolites, lepadins A and B. The structure and configuration of lepadin L were determined using HR-ESIMS and NMR spectroscopy. Further analysis showed that lepadin A had strong cytotoxic activity and could inhibit cell migration and clonogenity in A375 cells.
Article
Biochemistry & Molecular Biology
Costanza Vanni, Francesca Clemente, Paolo Paoli, Amelia Morrone, Camilla Matassini, Andrea Goti, Francesca Cardona
Summary: The synthesis of five new multivalent derivatives of a trihydroxypiperidine iminosugar was achieved through copper catalyzed alkyne-azide cycloaddition. These multivalent compounds showed much more potent inhibitory effects on lysosomal GCase, with the trivalent derivative demonstrating a 2-fold recovery of enzyme activity on Gaucher patient fibroblasts. Furthermore, thermal denaturation experiments indicated its ability to enhance stability of the recombinant enzyme used in therapy.
Article
Biochemistry & Molecular Biology
Francesca Clemente, Macarena Martinez-Bailen, Camilla Matassini, Amelia Morrone, Silvia Falliano, Anna Caciotti, Paolo Paoli, Andrea Goti, Francesca Cardona
Summary: This study reports the synthesis of five new trihydroxypiperidine iminosugars and identifies compound 12 as a potential therapeutic agent with chaperoning properties for GM1 gangliosidosis patients.
Article
Biochemistry & Molecular Biology
Claudia Capitini, Federica Feo, Anna Caciotti, Rodolfo Tonin, Matteo Lulli, Domenico Coviello, Renzo Guerrini, Martino Calamai, Amelia Morrone
Summary: This study established a feasible method for tracking changes in storage materials in frozen/thawed fibroblasts using fluorescent imaging and flow-cytometric methods. The results showed that our methods could effectively distinguish the levels of accumulated metabolites in fibroblasts from affected and unaffected patients for different lysosomal neurodegenerative conditions, indicating its potential application for other LSDs.
Article
Chemistry, Multidisciplinary
Francesca Clemente, Maria Giulia Davighi, Camilla Matassini, Francesca Cardona, Andrea Goti, Amelia Morrone, Paolo Paoli, Tomas Tejero, Pedro Merino, Martina Cacciarini
Summary: Piperidine-based photoswitchable derivatives have been developed as potential pharmacological chaperones for Gaucher disease. The compounds inhibit human GCase in a non-competitive manner, with the interaction occurring at an allosteric site. Experiments on GD patients' fibroblasts showed a moderate activity enhancement of the mutant GCase, indicating the potential for further improvement.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Chemistry, Organic
Costanza Vanni, Francesca Cardona, Francesca Clemente, Amelia Morrone, Martina Raudino, Moira Ambrosi, Pierandrea Lo Nostro, Camilla Matassini
Summary: Pharmacological chaperones are considered as an emerging therapy for Gaucher Disease. In this study, novel N-alkylated iminosugars were synthesized and characterized to investigate their biological activity. The results suggest that the C12 N-alkylated iminosugar 10 exerts its biological activity in the monomeric state.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Marta Vassallo, Daniele Martella, Gabriele Barrera, Federica Celegato, Marco Coisson, Riccardo Ferrero, Elena S. Olivetti, Adriano Troia, Huseyin Sozeri, Camilla Parmeggiani, Diederik S. Wiersma, Paola Tiberto, Alessandra Manzin
Summary: Magnetic hyperthermia is a therapeutic technique that utilizes magnetic nanoparticles to induce controlled temperature increase in diseased tissues. Surface treatments, such as using sodium citrate coating, can enhance the heat release capability of the nanoparticles and improve dispersion and stability in solution. Fe3O4 nanoparticles synthesized in this study exhibit an SLP value of around 170 W/g under a 100 kHz and 48 kA/m magnetic field.
Article
Nanoscience & Nanotechnology
Marta Rojas-Rodriguez, Tania Fiaschi, Michele Mannelli, Leonardo Mortati, Federica Celegato, Diederik S. Wiersma, Camilla Parmeggiani, Daniele Martella
Summary: Liquid Crystalline Networks (LCNs) with different surface topographies obtained by self-assembly can efficiently control cell alignment and differentiation, providing biological models that cannot be reproduced spontaneously on standard culture dishes. These materials can guide the organization of different cell lines, including single cell alignment or high-density cell cultures. The rough surfaces formed by the spontaneous assembly of liquid crystals can control biological models without the need for lithographic patterning or complex fabrication procedures, opening up possibilities for in vitro formation of well-aligned muscle tissue.
ACS APPLIED MATERIALS & INTERFACES
(2023)
Article
Agriculture, Dairy & Animal Science
F. Scicutella, M. A. Cucu, F. Mannelli, R. Pastorelli, M. Daghio, P. Paoli, L. Pazzagli, L. Turini, A. Mantino, S. Luti, M. Genovese, C. Viti, A. Buccioni
Summary: The study tested the use of olive oil pomace (OOP) produced by a new technology in dairy cow feeding and its effects on animal performance, rumen microbiota, biohydrogenation processes, and milk quality. The results showed that adding OOP improved the nutritional quality of milk and increased important functional fatty acid content without affecting animal performance and milk production.
Article
Chemistry, Organic
Macarena Martinez-Bailen, Camilla Matassini, Francesca Clemente, Cristina Faggi, Andrea Goti, Francesca Cardona
Summary: This study presents a novel stereoselective synthetic method for pentahydroxyazepaneiminosugars. The approach involves a crucial osmium-catalyzed aminohydroxylation reaction of allylic alcohols derived from the addition of vinylmagnesium bromide to a d-mannose-derived aldehyde. This reaction forms a new C-N bond with complete regio- and stereocontrol based on the tethering approach, followed by intramolecular reductive amination to obtain the desired azepanes. This is the first application of the osmium-catalyzed tethered aminohydroxylation reaction in the synthesis of iminosugars.
Article
Biology
Costanza Cicchi, Paolo Paoli, Alessandra Modesti, Federica Mannelli, Federica Scicutella, Arianna Buccioni, Carolina Fontanarosa, Simone Luti, Luigia Pazzagli
Summary: Transitioning to sustainable food systems involves the reuse of agricultural by-products as alternative feed ingredients, such as olive oil pomace, which can be used in the diet of lactating cows. Olive oil pomace supplementation does not negatively impact animal performance or rumen microbiota and even improves the fatty acid content of milk. The peptides derived from milk proteins of cows fed with olive oil pomace have potential antioxidant, anti-inflammatory, and anti-cancer effects, making them bioactive peptides. Incorporating agro-industrial by-products into dairy cow feeding strategies is a viable option for sustainable agriculture.
Article
Chemistry, Organic
Maria Giulia Davighi, Camilla Matassini, Andrea Goti, Marta Ferraroni, Andrea Angeli, Claudiu T. Supuran, Francesca Cardona
Summary: A series of novel mono- and three-tailed derivatives containing a sugar or an iminosugar with a terminal benzenesulfonamide were synthesized to investigate their inhibitory activity and selectivity towards human carbonic anhydrases (hCAs). Copper-catalyzed azide-alkyne cycloaddition followed by an amine-isothiocyanate coupling was used for synthesis. Biological assays revealed that the single-tailed sugar-based compound 10 exhibited better inhibition against three different hCAs compared to the reference compound (AAZ), while the three sugar tailed derivatives 25 and 26 showed potent and selective inhibition. The iminosugar single-tailed compound 31 exhibited promising and selective inhibitory activity towards hCA VII (Ki = 9.7 nM).
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
Francesca Buco, Camilla Matassini, Costanza Vanni, Francesca Clemente, Paolo Paoli, Cosimo Carozzini, Alice Beni, Francesca Cardona, Andrea Goti, Sergio Enrique Moya, Maria Grazia Ortore, Patrizia Andreozzi, Amelia Morrone, Marco Marradi
Summary: In this study, gold nanoparticles decorated with monosaccharides or sulfated ligands were designed as multivalent inhibitors for the enzyme GALNS associated with Morquio A. The beta-D-galactoside-coated AuNPs showed the most effective inhibition of GALNS activity. In the case of mixed-ligand AuNPs, alpha-D-mannosides exhibited a synergistic effect with sulfated ligands, leading to significantly stronger inhibition of GALNS.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
