Article
Biochemistry & Molecular Biology
Ginson George, Prashant S. Auti, Atish T. Paul
Summary: Pancreatic Lipase (PL) is an important enzyme for triglyceride digestion and its inhibition is considered as a potential approach for obesity management. Indole-thiazolidinedione hybrid analogues showed potent PL inhibitory activity, with compounds 6d and 6e exhibiting strong inhibitory effects in a competitive mode. Molecular modelling and fluorescence spectroscopic analysis confirmed the high binding affinity of these analogues with PL.
CHEMICAL BIOLOGY & DRUG DESIGN
(2021)
Article
Chemistry, Medicinal
Guang-Jing Feng, Yang-Fan Guo, Yuming Tang, Min Li, Yufei Jia, Zhimeng Li, Shuangshuang Wang, Hongmei Liu, Yuzhou Wu, Hai Dong
Summary: The potential of thioglucoside analogues as antidiabetic drugs was investigated in this study. The analogues showed good stability, low toxicity, and high inhibitory activity, making them promising candidates for new gliflozin drugs. Additionally, the synthesis of these analogues is simple, efficient, and cost-effective.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Yogesh Mahadu Khetmalis, Surendar Chitti, Anjani Umarani Wunnava, Banoth Karan Kumar, Muthyala Murali Krishna Kumar, Sankaranarayanan Murugesan, Kondapalli Venkata Gowri Chandra Sekhar
Summary: Thirty-four imidazo-[1,2-a)pyridine amides and imidazo[1,2-a]pyridine sulfonamides were designed and synthesized based on the molecular hybridization strategy. The compounds were evaluated for anti-tubercular activity and cytotoxicity, and their binding pattern and stability were studied using molecular docking and molecular dynamics simulations.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Gokhan Zengin, Dejan Stojkovic, Mohamad Fawzi Mahomoodally, Bibi Sharmeen Jugreet, Mehmet Yavuz Paksoy, Marija Ivanov, Uros Gasic, Monica Gallo, Domenico Montesano
Summary: This study demonstrated interesting bioactive components in two Seseli species, particularly polyphenolics, and showed several biological properties that could be further investigated for their potential exploitation as healing agents.
Article
Chemistry, Medicinal
Jifa Zhang, Lun Tan, Chengyong Wu, Yuyan Li, Hao Chen, Yinghuan Liu, Yuxi Wang
Summary: Novel 4,6-pyrimidine analogues were synthesized as colchicine binding site inhibitors (CBSIs) with strong antiproliferative activities. Among them, compound 17j showed the most potent activities against 6 human cancer cell lines, with IC50 values ranging from 1.1 nM to 4.4 nM, which was 76 times higher than the lead compound 3 in A549 cells. The co-crystal structure confirmed the key binding mode of 17j at the colchicine binding site. Furthermore, 17j inhibited tubulin polymerization, depolymerized cellular microtubules, induced G2/M arrest, inhibited cell migration, and promoted apoptosis. In vivo, 17j effectively inhibited primary tumor growth in the A549 xenograft model, with tumor growth inhibition rates of 42.51% (5 mg/kg) and 65.42% (10 mg/kg). Overall, 17j represents a promising new generation of CBSIs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Karolina Dzedulionyte, Nina Fuxreiter, Ekaterina Schreiber-Brynzak, Asta Zukauskaite, Algirdas Sackus, Verena Pichler, Egle Arbaciauskiene
Summary: A library of pyrazole-based lamellarin O analogues was synthesized via modification of easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates using bromination, N-alkylation, and Pd-catalysed Suzuki cross-coupling reactions. The synthesized compounds were evaluated for their physicochemical properties and cytotoxicity against colorectal cancer cell lines. The most active compounds exhibited cell proliferation inhibition in the low micromolar range and triggered cell death through G2/M-phase arrest.
Article
Biochemistry & Molecular Biology
Martin Juhas, Vinod S. K. Pallabothula, Katarina Grabrijan, Martina Simovicova, Ondrej Jandourek, Klara Konecna, Pavel Barta, Pavla Paterova, Stanislav Gobec, Izidor Sosic, Jan Zitko
Summary: Tuberculosis (TB) is the leading cause of death worldwide caused by a single infectious agent. The treatment of TB is complicated due to drug resistance, so new compounds with new mechanisms of action are needed. In this study, pyrazine-based inhibitors of the mycobacterial methionine aminopeptidase 1 (MtMetAP1) were designed, synthesized, and evaluated. The compounds showed high inhibition against the enzyme and moderate potency against Mycobacterium tuberculosis (Mtb), but no antibacterial or antifungal activity was observed.
BIOORGANIC CHEMISTRY
(2022)
Article
Plant Sciences
Shi-Xing Miao, Lin-Xi Wan, Zhen-Xiang He, Xian-Li Zhou, Xiaohuan Li, Feng Gao
Summary: The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was conducted, resulting in the synthesis of a new series of N-aryl-huperzine A analogues with good AChE inhibitory activity. Compound 30 showed the most potent AChE inhibition activity and could be a promising lead compound for Alzheimer's disease drug development.
JOURNAL OF NATURAL PRODUCTS
(2021)
Article
Chemistry, Medicinal
Carmen Lammi, Enrico M. A. Fassi, Marco Manenti, Marta Brambilla, Maria Conti, Jianqiang Li, Gabriella Roda, Marina Camera, Alessandra Silvani, Giovanni Grazioso
Summary: Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key target for the treatment of hypercholesterolemia and cardiovascular diseases. In this study, we discovered Rim13, a polyimidazole derivative that inhibits the interaction between PCSK9 and LDLR. Through computational design, we optimized the shape of PCSK9/ligand complementarity and identified potent diimidazole derivatives. Compound Dim16 showed improved PCSK9 inhibitory activity and some compounds in this series also showed hypocholesterolemic activity by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Guang Huan Shen, Joon Hee Hong
Summary: This review discusses the synthesis of five series of 4'-truncated nucleotide phosphonic acid analogues and briefly discusses their biological activity results.
CARBOHYDRATE RESEARCH
(2022)
Article
Chemistry, Multidisciplinary
Lin-Xi Wan, Shi-Xing Miao, Zhen-Xiang He, Xiaohuan Li, Xian-Li Zhou, Feng Gao
Summary: Efficient catalysis by Palladium/BuAd(2)P led to the synthesis of 15 aryldonepezil analogues with high selective AChE inhibition, among which the 3-methylpridinyl analogue (12) showed lower toxicity compared to donepezil and remarkable neuroprotective activity. Docking results of compound 12 provided insights into the selective inhibition mechanism between AChE and BuChE.
Article
Agriculture, Multidisciplinary
Jian-Jun Zhu, Pei-Yi Wang, Zhou-Qing Long, Shu-Zhen Xiang, Jun-Rong Zhang, Zhen-Xing Li, Yuan-Yuan Wu, Wu-Bin Shao, Xiang Zhou, Li-Wei Liu, Song Yang
Summary: In this study, small fragments were incorporated into 1,3,4-oxadiazole-2-carbohydrazides to expand their molecular diversity and screen potential succinate dehydrogenase inhibitors. Compound 10h showed strong inhibitory activity against Gibberella zeae and control activity against corn scab. It could also inhibit the enzymatic activity of SDH in the G. z. strain.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Chaoming Wang, Jinman Zhang, Xianfeng Wei, Mengke Yang, Weiping Ma, Rilei Yu, Ming Liu, Tao Jiang
Summary: In this study, 19 Lissodendrins B analogues were designed and synthesized, and their reversal activity of ATP-Binding Cassette Subfamily B Member 1 (ABCB1)-mediated multidrug resistance (MDR) was tested. Among them, compound D-1 showed the strongest synergistic effect with doxorubicin (DOX) and effectively reversed ABCB1-mediated drug resistance. Mechanistic studies revealed that the synergy was mainly due to the inhibition of ABCB1 efflux function, leading to increased intracellular accumulation of DOX. These findings suggest that compound D-1 and its derivatives have potential as MDR reversal agents by acting as ABCB1 inhibitors in clinical therapeutics.
Review
Biochemistry & Molecular Biology
Zefeng Zhao, Jiangxin Yue, Xiaotong Ji, Meng Nian, Kaiwen Kang, Haifa Qiao, Xiaohui Zheng
Summary: Succinimide derivatives have a variety of pharmacological properties in medicinal chemistry, with a growing number of derivatives being derived for potential targets.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Francesca Mancuso, Andrea Angeli, Viviana De Luca, Federica Bucolo, Laura De Luca, Clemente Capasso, Claudiu T. Supuran, Rosaria Gitto
Summary: This study reports on the screening process of inhibitors targeting carbonic anhydrases expressed in bacteria. By studying the inhibitory effects and selectivity of newly synthesized analogs, it was found that simple structural modifications can have a significant impact on inhibition and selectivity. Although the best active inhibitors showed high activity against bacterial carbonic anhydrases, they demonstrated a loss of selectivity towards human isozymes, highlighting the need for further development of more promising inhibitors.
ARCHIV DER PHARMAZIE
(2022)
Article
Oncology
Shalu Sharma Kharkwal, Christopher T. Johndrow, Natacha Veerapen, Himanshu Kharkwal, Noemi A. Saavedra-Avila, Leandro J. Carreno, Samantha Rothberg, Jinghang Zhang, Scott J. Garforth, Peter J. Jervis, Lianjun Zhang, Alena Donda, Amareeta K. Besra, Liam R. Cox, Steven C. Almo, Alan Howell, Elizabeth E. Evans, Maurice Zauderer, Gurdyal S. Besra, Steven A. Porcelli
Summary: A novel bispecific T-cell engager (BiTE) was developed to activate iNKT cells for antitumor immunity, enhancing multiple effector functions and promoting tumor-specific CD8(+) cytolytic T-cell responses. Simultaneous checkpoint blockade with anti-CTLA-4 antibodies further enhanced the antitumor effects, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs led to effective and nontoxic cancer immunotherapy regimens without inducing anergy or exhaustion in responding iNKT cells.
Article
Biochemistry & Molecular Biology
Natacha Veerapen, Judith Hobrath, Amareeta K. Besra, Gurdyal S. Besra
Summary: MAIT cells represent a potential therapeutic target for tuning or enhancing immune responses, and a better understanding of the MAIT cell-MR1-antigen interaction is crucial for assessing their significance in human diseases. Easy access to MR1 ligands and MAIT cells activators can help achieve this goal.
MOLECULAR IMMUNOLOGY
(2021)
Article
Chemistry, Medicinal
Shipra Grover, Curtis A. Engelhart, Esther Perez-Herran, Wei Li, Katherine A. Abrahams, Kadamba Papavinasasundaram, James M. Bean, Christopher M. Sassetti, Alfonso Mendoza-Losana, Gurdyal S. Besra, Mary Jackson, Dirk Schnappinger
Summary: A novel guanidine-based MmpL3 inhibitor was identified successfully through a cell-based assay utilizing two-way regulation of MmpL3 expression. Additionally, inhibitors of cytochrome bc(1)-aa(3) oxidase and a novel sulfanylacetamide as a potential QcrB inhibitor were discovered in whole-cell screens for MmpL3 inhibitors.
ACS INFECTIOUS DISEASES
(2021)
Article
Biochemistry & Molecular Biology
Corinna A. Kulicke, Erica De Zan, Zeynep Hein, Claudia Gonzalez-Lopez, Swapnil Ghanwat, Natacha Veerapen, Gurdyal S. Besra, Paul Klenerman, John C. Christianson, Sebastian Springer, Sebastian M. Nijman, Vincenzo Cerundolo, Mariolina Salio
Summary: The MR1-MAIT cell axis is involved in various diseases, and this study discovered that ATP13A1 in the endoplasmic reticulum is a key factor in MR1 surface expression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Rongfei Qin, Pengxu Wang, Bin Wang, Lei Fu, Sarah M. Batt, Gurdyal S. Besra, Chengwei Wu, Yanan Wang, Haihong Huang, Yu Lu, Gang Li
Summary: A series of thiophene-benzenesulfonamide derivatives were designed and synthesized to explore their structure-activity relationship as antituberculosis agents. Compound 17b showed improved activity compared to the lead compounds, displaying good intracellular antimycobacterial activity and favorable drug properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Immunology
Noemi Alejandra Saavedra-Avila, Paolo Dellabona, Giulia Casorati, Natacha Veerapen, Gurdyal S. Besra, Amy R. Howell, Steven A. Porcelli
Summary: A genetically modified mouse model allows for more accurate prediction of human iNKT cell responses, providing opportunities for preclinical evaluation of iNKT cell-based therapies.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Carl J. H. Wang, Wael Awad, Ligong Liu, Jeffrey Y. W. Mak, Natacha Veerapen, Patricia T. Illing, Anthony W. Purcell, Sidonia B. G. Eckle, James McCluskey, Gurdyal S. Besra, David P. Fairlie, Jamie Rossjohn, Jerome Le Nours
Summary: In this study, we developed a fluorescence polarization-based assay to quantitatively evaluate the binding affinity of MR1 ligands. With this method, we successfully categorized ligands as strong, moderate, or weak binders to MR1, and identified two dietary compounds as weak MR1 ligands.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Microbiology
Sarah M. Batt, Szilvi Toth, Beatriz Rodriguez, Katherine A. Abrahams, Natacha Veerapen, Giacomo Chiodarelli, Liam R. Cox, Patrick J. Moynihan, Joel Lelievre, Klaus Futterer, Gurdyal S. Besra
Summary: DprE2 is an important enzyme for the synthesis of DPA and arabinogalactan, making it a significant drug target for M. tuberculosis. Two compounds from the GSK-177 box set, GSK301A and GSK032A, were identified through overexpression studies of Mt-DprE2 target. The Mt-DprE1-DprE2 complex was purified and a new in vitro DprE2 assay was developed, based on the oxidation of the reduced nicotinamide adenine dinucleotide cofactor. Although no inhibition was observed by the two GSK compounds in the DprE2 assay, spontaneous mutant generation suggested a possible pro-drug activation pathway involving fgd1 and fbiC.
Article
Microbiology
Alexander D. H. Kingdon, Asti-Rochelle Meosa-John, Sarah M. Batt, Gurdyal S. Besra
Summary: Mycobacterium tuberculosis is a deadly pathogen causing tuberculosis infections and the leading cause of death globally from a single infectious agent. The identification of additional drugs and the development of strategies to combat drug resistance are crucial in achieving the goals of the End TB 2030 strategy. Vanoxerine, a dopamine re-uptake inhibitor, has been found to have anti-mycobacterial activity, disrupting the membrane electric potential and inhibiting mycobacterial growth without detectable resistance, suggesting its potential as a tool compound or for further development.
FRONTIERS IN MICROBIOLOGY
(2023)
Review
Chemistry, Medicinal
Saloni Yadav, Aastha Soni, Omprakash Tanwar, Rajendra Bhadane, Gurdyal S. Besra, Neha Kawathekar
Summary: This review provides an in-depth analysis of the structural requirements for DprE1 inhibitors, including both covalent and non-covalent inhibitors, their binding patterns, and their biological activity data in vitro and in vivo. It also introduces a protein quality score (PQS) and an active-site map of the DprE1 enzyme to aid in the development of new anti-TB drugs.
Article
Multidisciplinary Sciences
Yicheng Gong, Chuancun Wei, Jun Wang, Nengjiang Mu, Qinhong Lu, Chengyao Wu, Ning Yan, Huifang Yang, Yao Zhao, Xiuna Yang, Sudagar S. Gurcha, Natacha Veerapen, Sarah M. Batt, Zhiqiang Hao, Lintai Da, Gurdyal S. Besra, Zihe Rao, Lu Zhang
Summary: Arabinogalactan (AG) is an essential component in mycobacterial species, and AftA is a key enzyme involved in AG biosynthesis. The cryo-EM structure of Mtb AftA reveals its dimeric assembly and the participation of a metal ion in its interaction. Structural analysis and mutagenesis studies provide insights into the priming mechanism catalyzed by AftA in Mtb AG biosynthesis, which can contribute to anti-TB drug discovery.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Nidhi Kedia-Mehta, Marta M. Pisarska, Christina Rollings, Chloe O'Neill, Conor De Barra, Cathriona Foley, Nicole A. W. Wood, Neil Wrigley-Kelly, Natacha Veerapen, Gurdyal Besra, Ronan Bergin, Nicholas Jones, Donal O'Shea, Linda V. Sinclair, Andrew E. Hogan
Summary: In this study, it was found that the activation of MAIT cells leads to increased abundance of MYC, a key metabolic regulator and transcription factor. Two MYC-controlled metabolic pathways, amino acid transport and glycolysis, were found to be necessary for MAIT cell proliferation. The study also showed that MAIT cells from obese individuals have decreased MYC abundance upon activation, resulting in impaired cell proliferation and function.
Article
Medicine, Research & Experimental
Suzanne E. Engelen, Francesca A. Ververs, Angela Markovska, B. Christoffer Lagerholm, Jordan M. Kraaijenhof, Laura I. E. Yousif, Yasemin-Xiomara Zurke, Can M. C. Gulersonmez, Sander Kooijman, Michael Goddard, Robert J. van Eijkeren, Peter J. Jervis, Gurdyal S. Besra, Saskia Haitjema, Folkert W. Asselbergs, Eric Kalkhoven, Hidde L. Ploegh, Marianne Boes, Vincenzo Cerundolo, G. K. Hovingh, Mariolina Salio, Edwin C. A. Stigter, Patrick C. N. Rensen, Claudia Monaco, Henk S. Schipper
Summary: This study reveals that circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by antigen-presenting cells, leading to enhanced iNKT cell activation. This discovery uncovers a novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.
Article
Immunology
Andrew Chancellor, Robert Alan Simmons, Rahul C. Khanolkar, Vladimir Nosi, Aisha Beshirova, Giuliano Berloffa, Rodrigo Colombo, Vijaykumar Karuppiah, Johanne M. Pentier, Vanessa Tubb, Hemza Ghadbane, Richard J. Suckling, Keith Page, Rory M. Crean, Alessandro Vacchini, Corinne De Gregorio, Verena Schaefer, Daniel Constantin, Thomas Gligoris, Angharad Lloyd, Miriam Hock, Velupillai Srikannathasan, Ross A. Robinson, Gurdyal S. Besra, Marc W. Van der Kamp, Lucia Mori, Raffaele Calogero, David K. Cole, Gennaro De Libero, Marco Lepore
Summary: Canonical MAIT TCRs with dual reactivity to microbial and self-antigens can recognize MR1 promiscuously, allowing MAIT cell responses in the absence of microbial infection. MAIT TCRs can also crossreact with self-antigens and perform T-helper-like functions in vitro. The promiscuity of MR1 recognition by a canonical MAIT TCR is associated with unique TCR β-chain features enriched in self-reactive MAIT cells of healthy individuals. These findings suggest a broader role of MAIT cells in immune homeostasis and diseases beyond microbial immunosurveillance.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Katherine A. Abrahams, Sarah M. Batt, Sudagar S. Gurcha, Natacha Veerapen, Ghader Bashiri, Gurdyal S. Besra
Summary: This study identifies an enzyme required for the synthesis of the mycobacterial cell wall as the target of Pretomanid and delamanid, two pro-drugs used for tuberculosis treatment. The findings provide valuable insights into the mechanisms of action and potential clinical applications of these drugs.
NATURE COMMUNICATIONS
(2023)
