Article
Chemistry, Multidisciplinary
Manuel Scherer, Andres G. Santana, Kyle Robinson, Steven Zhou, Hermen S. Overkleeft, Lorne Clarke, Stephen G. Withers
Summary: This study introduces a new class of transient GCase inactivators with improved stability in aqueous media, and validates through cellular research that treatment with these compounds can restore catalytic activity in Gaucher cells.
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
Biotechnology & Applied Microbiology
Tomohiko Matsuzawa, Masahiro Watanabe, Yusuke Nakamichi, Hironaga Akita, Katsuro Yaoi
Summary: This paper reports the crystal structures of Metagenomic MeBglD2 complexed with various saccharides, revealing its substrate recognition mechanism. The subsite -1 of MeBglD2 is structurally similar to other GH1 enzymes, but the binding modes of the positive subsites vary depending on the type of sugar. Three residues (Glu183, Asn227, and Asn229) located at the positive subsites of MeBglD2 are involved in substrate specificity in the presence of additive sugars. Docking simulation suggests that Asn229 and Trp329 play key roles in recognizing the +1 D-glucose in cellobiose.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2022)
Article
Chemistry, Physical
Jing-Jing Chen, Xiao Liang, Tian-Jiao Chen, Jin-Ling Yang, Ping Zhu
Summary: The beta-glycosidase LXYL-P1-2 from Lentinula edodes can hydrolyze XDT into DT for Taxol semi-synthesis. Introducing the L220G mutation increases enzyme activity, and the subsequent mutant GS115-EP2-L220G shows nearly double the beta-D-xylosidase activity compared to LXYL-P1-2, providing a candidate strain for industrial production and a basis for exploring key amino acid residues in LXYL-P1-2.
Article
Chemistry, Multidisciplinary
Tomas Klunda, Michal Hricovini, Sergej Sestak, Juraj Kona, Monika Polakova
Summary: In this study, N-alkylated polyhydroxypyrrolidines were synthesized and tested as inhibitors of Golgi alpha-mannosidase II (GMIIb). The potency of the inhibitors varied depending on the alkyl chain length and capping functional group, with amidines showing the highest activity. Molecular docking and quantum mechanics calculations revealed the importance of alkyl chain length in the interactions with the target enzyme.
NEW JOURNAL OF CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Arnold E. Stuetz, Martin Thonhofer, Patrick Weber, Andreas Wolfsgruber, Tanja M. Wrodnigg
Summary: The article presents a brief survey on selected beta-galactosidase inhibitors as potential pharmacological chaperones for G(M1)-gangliosidosis and Morquio B associated mutants of human lysosomal beta-galactosidase, highlighting recent developments in this specific area of lysosomal storage disorders and orphan diseases.
Review
Biochemistry & Molecular Biology
Chen Chen, Pinglong Xu
Summary: Inflammasomes are intracellular signaling complexes involved in inflammatory reactions and cytokine release. They play a role in various diseases and have potential as therapeutic targets.
Article
Chemistry, Applied
Di Wu, Lan Tang, Ran Duan, Xia Hu, Fang Geng, Yin Zhang, Lianxin Peng, Hui Li
Summary: This study investigated the interaction mechanisms between Hyperoside and two main soy proteins, showing that Hyperoside is stably located in the hydrophobic pockets of beta-conglycinin and glycinin. The conformation and microenvironment of the proteins changed after binding to Hyperoside, with a good affinity observed at 4 degrees C. The results suggest the potential for constructing an embedding and delivery system to enhance the benefits of Hyperoside in high value-added food products.
Article
Chemistry, Medicinal
Sean P. Henry, William L. Jorgensen
Summary: The Janus kinases (JAKs) play important roles in the JAK-STAT signaling pathway and are involved in various physiological processes. Although they are targeted by FDA-approved drugs, these drugs often have adverse effects due to their inhibition of JAK kinase activity. However, JAKs have a unique pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). Targeting the JH2 domain may provide an alternative approach to modulate JAKs without the associated adverse effects. The recent FDA approval of deucravacitinib, a JH2 ligand, for treating plaque psoriasis demonstrates the potential of this strategy.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Renata Collard, Tomas Majtan
Summary: Homocystinuria is an inherited metabolic disorder caused by lack of cystathionine beta-synthase (CBS) activity. This study found that pathogenic CBS variants result in dysregulation of gene expression of small heat shock proteins and HSP40 family members, as well as endoplasmic reticulum stress and protein degradation. Manipulation of cellular proteostasis could rescue CBS variant function and potentially serve as a therapeutic approach for treating HCU.
MOLECULAR AND CELLULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Cristina Martin-Escura, M. angeles Bonache, Jessy A. Medina, Alicia Medina-Peris, Jorge De Andres-Lopez, Sara Gonzalez-Rodriguez, Sara Kerselaers, Gregorio Fernandez-Ballester, Thomas Voets, Antonio Ferrer-Montiel, Asia Fernandez-Carvajal, Rosario Gonzalez-Muniz
Summary: This study describes the synthesis and evaluation of novel TRPM8 antagonist derivatives, as well as their inhibition on cellular Ca2+ entry and selectivity. The most effective compounds demonstrated potent antagonist activity through experimental validation and showed significant antinociceptive activity in a cold pain model in vivo.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Li-Zhi Cheng, Dan-Ling Huang, Zhang-Rui Tang, Jia-Hao Zhang, Ting Xiong, Chen Zhou, Nai-Xia Zhang, Rong Fu, Yong-Xian Cheng, Zhao-Qiu Wu
Summary: A small-molecule compound, CW85319, was found to enhance the interaction between Axin2 and GSK3 beta, leading to the phosphorylation, ubiquitination, and degradation of Axin2. This compound effectively suppressed the growth and metastasis of colorectal cancer cells and may serve as a potential therapeutic target for certain human cancers, especially colorectal cancer.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Oncology
Sofia Xanthoulea, Gonda F. J. Konings, Niina Saarinen, Bert Delvoux, Loes F. S. Kooreman, Pasi Koskimies, Merja R. Hakkinen, Seppo Auriola, Elisabetta D'Avanzo, Youssef Walid, Frank Verhaegen, Natasja G. Lieuwes, Florian Caiment, Roy Kruitwagen, Andrea Romano
Summary: The study demonstrates that pharmacological inhibition of 17β-HSD-1 can inhibit the development of endometrial cancer. Through experiments on mice, it was found that treatment with the inhibitor significantly reduces tumor growth and metastatic spread.
Article
Medicine, Research & Experimental
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Scott Arthur Scarneo, Philip Hughes, M. Asif Amin, Pei-Suen Tsou, Dinesh Khanna, Timothy A. J. Haystead, Swati Bhattacharyya, John Varga
Summary: Multiorgan fibrosis in systemic sclerosis (SSc), a disease lacking effective treatments and with high mortality, might be influenced by the TGF-β and TLR signaling pathway, particularly through TAK1. The inhibition of TAK1 using HS-276 showed promising results in reducing fibrosis and profibrotic mediators in both in vitro and in vivo experiments, suggesting it as a potential strategy for the treatment of SSc and other fibrotic diseases.
Article
Biochemistry & Molecular Biology
Roohi Parveen, Mohd. Kashif, Hemalatha Srinivasan, Jasim Khan, Amar Yousif, Dina Saeed Ghataty, Nemat Ali, Sabry M. Attia, Mohammad Waseem
Summary: Inflammatory signals are considered as a key for pharmacological interventions. Several compounds have been identified as promising medications against inflammation and its associated chronic disorders. Inflammasomes have been recognized as triggers for detrimental stimuli and have been implicated in the progression of GBM. Our in silico investigations have identified powerful pharmacological agents/compounds against inflammasome-mediated GBM.
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jerome Desire, Quentin Foucart, Ana Poveda, Gurvan Gourlaouen, Yuna Shimadate, Maki Kise, Cameron Proceviat, Roger Ashmus, David J. Vocadlo, Jesus Jimenez-Barbero, Atsushi Kato, Yves Bleriot
Summary: A series of bicyclic iminosugar C-glycosides based on an octahydrofuro[3,2-b]pyridine motif have been synthesized. These carbohydrate mimics showed promising inhibitory activity against glycosidases, suggesting their potential for drug development.
CARBOHYDRATE RESEARCH
(2022)
Article
Chemistry, Medicinal
Atsushi Kato, Izumi Nakagome, Uta Kanekiyo, Tian-Tian Lu, Yi-Xian Li, Kosuke Yoshimura, Mana Kishida, Kenta Shinzawa, Tomoki Yoshida, Nobutada Tanaka, Yue-Mei Jia, Robert J. Nash, George W. J. Fleet, Chu-Yi Yu
Summary: In recent years, pharmacological chaperones have been recognized as thermodynamic stabilizers in combination therapy. This study focused on designing a high-affinity ligand for lysosomal acid alpha-glucosidase (GAA) using alkyl branches on 1-deoxynojirimycin (DNJ). The results showed that 5-C-heptyl-DNJ significantly improved the stability of recombinant human acid alpha-glucosidase (rhGAA) and increased intracellular GAA activities in cells from Pompe disease patients.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
J. Bouquet, N. Auberger, R. Ashmus, D. King, A. Bordes, N. Fontelle, S. Nakagawa, Z. Madden, C. Proceviat, A. Kato, J. Desire, D. J. Vocadlo, Y. Bleriot
Summary: The synthesis and evaluation of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold as inhibitors of functionally related exo-N-acetylhexosaminidases were reported. The study explored the effects of epimerization and C-alkylation at specific positions, leading to the identification of selective inhibitors for different hexosaminidases.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Katsuki Takashima, Takuya Okada, Atsushi Kato, Yuhei Yamasaki, Takeshi Sugouchi, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya, Hiroyuki Morita, Takuya Ito, Takeshi Kodama, Genzoh Tanabe, Naoki Toyooka
Summary: In this study, the divergent synthesis of various poison-frog alkaloids was achieved using stereoselective reactions, resulting in the discovery of potential compounds with inhibitory activity against the cholinergic nervous system.
Article
Chemistry, Medicinal
Jun-Zhe Wang, Yuna Shimadate, Maki Kise, Atsushi Kato, Yue-Mei Jia, Yi-Xian Li, George W. J. Fleet, Chu-Yi Yu
Summary: Enantiomeric series of C-4 hydroxymethyl depleted DAB and LAB derivatives were synthesized and evaluated as potent and selective GCase inhibitors. The study provides a strategy for the development of drugs for the treatment of acid beta-glucosidase related diseases.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jun-Zhe Wang, Bin Cheng, Atsushi Kato, Maki Kise, Yuna Shimadate, Yue-Mei Jia, Yi-Xian Li, George W. J. Fleet, Chu-Yi Yu
Summary: This study designed and synthesized two series of C-4 alkylated and arylated LAB and DAB derivatives, and evaluated their activity against various glycosidases. The results revealed potential inhibitory effects of some derivatives and provided guidance for drug design and development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(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
Biochemistry & Molecular Biology
David M. Campkin, Yuna Shimadate, Barbara Bartholomew, Paul Bernhardt, Robert J. Nash, Jennette A. Sakoff, Atsushi Kato, Michela Simone
Summary: Novel tetrachlorinated phthalimide analogues with boron-pinacolate ester group were synthesized and evaluated for their potential applications in glycosidase modulation and cancer treatment, showing promising potency and selectivity for certain molecules.
Article
Chemistry, Organic
Koichi Narita, Shotaro Yoshida, Hiroka Satoh, Kazuhiro Watanabe, Yuichi Yoshimura
Summary: In this study, the optically active form of the hexahydrobenzofurobenzopyran ring, found in naturally occurring bisabosquals, was synthesized for the first time. The synthetic route involved three key steps: induction of chirality, transfer of chirality, and stepwise construction of the hexahydrobenzofurobenzopyran skeleton. Both the racemic and optically active hexahydrobenzofurobenzopyrans were obtained using this synthetic route.
Article
Chemistry, Medicinal
Dong Zi, Ying-Ying Song, Tian-Tian Lu, Maki Kise, Atsushi Kato, Jun-Zhe Wang, Yue-Mei Jia, Yi-Xian Li, George W. J. Fleet, Chu-Yi Yu
Summary: A series of alpha-1-C-alkyl DAB and LAB derivatives have been designed as analogues of broussonetine W and assayed as glycosidase inhibitors. Introducing substituents on the terminal aryl or hydroxyl groups decreased their alpha-glucosidase inhibitions but improved their inhibitions of bovine liver beta-glucosidase and beta-galactosidase. The compounds also showed potent inhibitions of human lysosome beta-glucosidase and docking calculations revealed novel binding modes.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Atsushi Kato, Izumi Nakagome, Maki Kise, Kousuke Yoshimura, Nobutada Tanaka, Robert J. Nash, George W. J. Fleet, Yota Kobayashi, Hayato Ikeda, Takuya Okada, Naoki Toyooka
Summary: This study presents a strategy for designing a practical ligand for lysosomal acid alpha-glucosidase (GAA) with a focus on N-alkyl derivatives of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). The optimized N-4'-(p-trifluoromethylphenyl)butyl-DAB (5g) showed significantly higher affinity for GAA compared to N-butyl-DAB (3f). Docking analysis revealed the accommodation of the phenyl group of 5g in a lipophilic pocket and the stabilizing effect of the p-trifluoromethyl group.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Plant Sciences
Brendan J. Byatt, Atsushi Kato, Stephen G. Pyne
Summary: The 10 glyphaeaside alkaloids isolated from the roots of Glyphaea brevis were originally believed to be piperidine-based 1-C-alkylated iminosugars with different ring configurations. However, further studies showed that glyphaeaside C is a pyrrolidine-based iminosugar with a revised ring configuration. Synthesis experiments were conducted to confirm the structure of glyphaeaside C and related derivatives. The inhibitory activity of these compounds against glycosidases was also examined, revealing their potential as inhibitors.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Biochemistry & Molecular Biology
Jerome Desire, Zakaria Debbah, David Gueyrard, Jerome Marrot, Yves Bleriot, Atsushi Kato
Summary: A series of L-iminosugar C,C-glycosides containing an allyl group and various substituents at the pseudoanomeric position were synthesized and evaluated for their glycosidase inhibition activity. The compounds adopted a 1C4 conformation and showed weaker glycosidase inhibition compared to previously reported branched L-iminosugars. However, some compounds exhibited micromolar inhibition of human lysosome β-glucocerebrosidase, indicating their potential as potent CGase inhibitors by modifying the structure/length of the pseudoanomeric substituents.
CARBOHYDRATE RESEARCH
(2023)
Article
Chemistry, Organic
Dong Zi, Yuna Shimadate, Jun-Zhe Wang, Atsushi Kato, Yi-Xian Li, Yue-Mei Jia, George W. J. Fleet, Chu-Yi Yu
Summary: A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from d-tartrate-derived nitrone 18. Four of the DAB peptides were found to be weak and selective bovine liver beta-galactosidase inhibitors, with the compound 23b showing the most potent beta-galactosidase inhibition. Molecular docking studies revealed different docking modes of compound 23b compared to other DAB peptides, and partial similarity of compound 23b to DGJ.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
Atsushi Kato, Izumi Nakagome, Kosuke Yoshimura, Uta Kanekiyo, Mana Kishida, Kenta Shinzawa, Tian-Tian Lu, Yi-Xian Li, Robert J. Nash, George W. J. Fleet, Nobutada Tanaka, Chu-Yi Yu
Summary: This study demonstrates a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and l-sugar-type iminosugars to change the orientation of binding. The designed ligand, 5-C-methyl-l-ido-DNJ, showed strong affinity for GAA and enhanced enzyme activity and transport in Pompe patient cells.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
