Article
Chemistry, Medicinal
William H. Parsons, Nicholas T. Rutland, Jennifer A. Crainic, Joaquin M. Cardozo, Alyssa S. Chow, Charlotte L. Andrews, Brendan K. Sheehan
Summary: Using activity-based protein profiling technology, we identified a series of sulfonyl esters and sulfonamides as inhibitors of the mitochondrial rhomboid protease PARL. These compounds showed high selectivity for PARL over the bacterial rhomboid protease GlpG. The reversible binding of these compounds to PARL in mammalian cells suggests their potential as PARL-selective inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Jian Yang, Luis A. R. Carvalho, Shanping Ji, Suyuan Chen, Rui Moreira, Steven H. L. Verhelst
Summary: In this study, 4-oxo-beta-lactams are identified as a novel scaffold for inhibition of rhomboid proteases, and they may serve as both inhibitors and activity-based probes for rhomboid proteases.
Article
Chemistry, Multidisciplinary
Tim Van Kersavond, Raphael Konopatzki, Merel A. T. van der Plassche, Jian Yang, Steven H. L. Verhelst
Summary: Rhomboid proteases are important enzymes involved in various biological processes and human diseases. Recent research has shown that solid-phase synthesis of peptidyl alpha-ketoamides allows rapid synthesis and optimization of rhomboid protease inhibitors, with the primed site binding part being crucial for potency.
Article
Multidisciplinary Sciences
Claudia Bohg, Carl Oster, Berke Turkaydin, Michael Lisurek, Pascal Sanchez-Carranza, Sascha Lange, Tillmann Utesch, Han Sun, Adam Lange
Summary: Rhomboid proteases hydrolyze substrate helices within the lipid bilayer to release soluble domains from the membrane. The lateral gate formed by TM2 and TM5 in the model rhomboid GlpG allows access of the hydrophobic substrate to the active site. The opening dynamics of the lateral gate in rhomboid proteases strongly affects their enzymatic activity.
Article
Multidisciplinary Sciences
Mohamed H. Baren, Seham A. Ibrahim, Munirah M. Al-Rooqi, Saleh A. Ahmed, Mohammed M. El-Gamil, Hend A. Hekal
Summary: In this study, a new series of α-aminophosphonates derivatives were synthesized and evaluated for their anticancer activities. Some compounds exhibited stronger inhibitory activity than Doxorubicin, and were found to potentially function as VEGFR2 and FGFR1 inhibitors.
SCIENTIFIC REPORTS
(2023)
Review
Pharmacology & Pharmacy
Abdur Rauf, Anees Ahmed Khalil, Ahmed Olatunde, Muneeb Khan, Sirajudheen Anwar, Ahmed Alafnan, Kannan R. R. Rengasamy
Summary: Marine habitats are rich in diverse life forms that offer potential sources of novel bioactive compounds, including protease inhibitors with significant applications in pharmaceutical, nutraceutical, and cosmeceutical industries. Despite extensive research on protease inhibitors, many compounds have not advanced to clinical trials, highlighting the ongoing need for exploring new sources for their development.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Biochemical Research Methods
Chathura Paththamperuma, Richard C. Page
Summary: This study describes the development and implementation of a fluorescence dequenching-based assay to quantify the activity of TEV protease. The assay proved to be a rapid and simple method for evaluating TEV protease activity in purified samples and crude lysate extracts, providing useful kinetic data for improved TEV protease variants and determining the optimum pH for TEV protease reactions.
ANALYTICAL BIOCHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Jingxin Qiao, Yue-Shan Li, Rui Zeng, Feng-Liang Liu, Rong-Hua Luo, Chong Huang, Yi-Fei Wang, Jie Zhang, Baoxue Quan, Chenjian Shen, Xin Mao, Xinlei Liu, Weining Sun, Wei Yang, Xincheng Ni, Kai Wang, Ling Xu, Zi-Lei Duan, Qing-Cui Zou, Hai-Lin Zhang, Wang Qu, Yang-Hao-Peng Long, Ming-Hua Li, Rui-Cheng Yang, Xiaolong Liu, Jing You, Yangli Zhou, Rui Yao, Wen-Pei Li, Jing-Ming Liu, Pei Chen, Yang Liu, Gui-Feng Lin, Xin Yang, Jun Zou, Linli Li, Yiguo Hu, Guang-Wen Lu, Wei-Min Li, Yu-Quan Wei, Yong-Tang Zheng, Jian Lei, Shengyong Yang
Summary: The study designed and synthesized 32 new M-pro inhibitors containing bicycloproline, which showed inhibitory effects on SARS-CoV-2. Compounds MI-09 and MI-30 exhibited excellent antiviral activity in cell-based assays and significantly reduced lung viral loads and lung lesions in a transgenic mouse model of SARS-CoV-2 infection. Both also displayed good pharmacokinetic properties and safety in rats.
Article
Chemistry, Multidisciplinary
Isis Maximo Dantas Feitosa, Ronnie Emanuel Pereira Pinto, Matheus Mendonca Pereira, Cleide Mara Faria Soares, Alvaro Silva Lima
Summary: This study optimized the extraction of proteins from Brazilwood seeds with proteolytic inhibitory activity using choline-based ionic liquid. The best extraction conditions were 25.42 degrees C, 5.42% (m/v) choline bitartrate, solid-liquid ratio 1:5, 500 rpm and pH 7.0. Under optimized conditions, the protein extract of Brazilwood seeds provided a 60.8% inhibition of trypsin.
SUSTAINABLE CHEMISTRY AND PHARMACY
(2023)
Article
Chemistry, Medicinal
Carina Lemke, Jakub Benysek, Dominik Brajtenbach, Christian Breuer, Adela Jilkova, Martin Horn, Michal Busa, Lenka Ulrychova, Annika Illies, Katharina F. Kubatzky, Ulrike Bartz, Michael Mares, Michael Guetschow
Summary: The cysteine protease cathepsin K is a key target for diseases related to bone turnover, and the study successfully designed a potent fluorescent activity-based probe for inactivating cathepsin K. The crystal structures of cathepsin K bound to the probe provided insights into its binding mode, demonstrating its potential for application in pathophysiological environments.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Timothy E. G. Ferguson, James A. Reihill, S. Lorraine Martin, Brian Walker
Summary: Serine proteases play varied and important roles in biological processes, and activity-based profiling has been instrumental in pinpointing their precise roles. A range of activity-based probes targeting serine proteases have been developed, and their synthesis and application in profiling various serine proteases are described in this study.
FRONTIERS IN CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Abdeslem Bouzina, Yousra Ouafa Bouone, Omar Sekiou, Mohamed Aissaoui, Tan-Sothea Ouk, Abdelhak Djemel, Rachida Mansouri, Malika Ibrahim-Ouali, Zihad Bouslama, Nour-Eddine Aouf
Summary: The study aims to evaluate cyclosulfamide-based molecules as potential anticancer agents through in silico and experimental methods. The cytotoxic activity of enastron analogues on three human cell lines derived from B-cell lymphoma, acute T cell leukaemia, and chronic myelogenous leukaemia was investigated. Most of the tested compounds showed good inhibitory activity, with the 5a derivative demonstrating the strongest effect. Molecular docking simulations and molecular dynamics simulations revealed the ability of the studied molecules to inhibit the Eg5 enzyme. DFT calculations were used to analyze the electronic and geometric characteristics of the compounds, and ADME prediction was also studied.
Review
Biochemistry & Molecular Biology
Olja Mijanovic, Aleksandra Jakovleva, Ana Brankovic, Kristina Zdravkova, Milena Pualic, Tatiana A. Belozerskaya, Angelina Nikitkina, Alessandro Parodi, Andrey A. Zamyatnin
Summary: In this review, we summarized the molecular background, involvement in various diseases, and clinical significance for diagnosis and therapy of Cathepsin K (CatK).
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Andreza do Socorro Silva da Veiga, Fernando Tobias Silveira, Edilene Oliveira da Silva, Jose Antonio Picanco Diniz Junior, Sanderson Correa Araujo, Marliane Batista Campos, Andrey Moacir do Rosario Marinho, Geraldo Celio Brandao, Valdicley Vieira Vale, Sandro Percario, Maria Fani Dolabela
Summary: This study evaluated the morphological changes caused by fractions and subfractions obtained from barks of Aspidosperna nitidum against L. (L.) amazonensis promastigotes. The results suggest that alkaloids isolated from A. nitidum show potential as leishmanicidal agents. Scanning electron microscopy and transmission electron microscopy analysis revealed changes in the parasites' morphology after treatment with the active fractions.
SCIENTIFIC REPORTS
(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
Biochemistry & Molecular Biology
Jian Yang, Rafal J. Mendowicz, Steven H. L. Verhelst
Summary: Activity-based probes (ABPs) are valuable chemical tools for profiling enzymes, particularly proteases. Alkyne-substituted benzoxazin-4-ones can covalently inhibit serine proteases and be used for labeling and identifying various serine proteases, offering easily synthesizable tools for their profiling.
Review
Biochemistry & Molecular Biology
Dimitris Korovesis, Hester A. Beard, Christel Merillat, Steven H. L. Verhelst
Summary: This review discusses the design principles and applications of probes for the photoaffinity labelling of kinases, highlighting their importance in research and drug development. Insights from crystal structures have guided the development of a wide variety of probes for studying kinase members.
Article
Biology
Marta Barniol-Xicota, Steven H. L. Verhelst
Summary: The study found that maleic acid based copolymers can disrupt lipid bilayers and form lipid protein nanodiscs soluble in aqueous buffer. The content of xMALPs varies depending on the chemical properties of the used xMA.
COMMUNICATIONS BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Nicole Rufo, Dimitris Korovesis, Sofie Van Eygen, Rita Derua, Abhishek D. Garg, Francesca Finotello, Monica Vara-Perez, Jan Rozanc, Michael Dewaele, Peter A. de Witte, Leonidas G. Alexopoulos, Sophie Janssens, Lasse Sinkkonen, Thomas Sauter, Steven H. L. Verhelst, Patrizia Agostinis
Summary: Immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress stimulate immunomodulatory/proinflammatory factors by stressed cancer cells, with NF-kappa B/AP-1 inflammatory stress response being a key mechanism. However, the anti-inflammatory effect of IRE1 alpha kinase inhibitor KIRA6 can impact inflammation responses, urging caution in interpreting its action.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Chemistry, Multidisciplinary
Bing-Yu Li, Lauren Voets, Ruben Van Lommel, Fien Hoppenbrouwers, Mercedes Alonso, Steven H. L. Verhelst, Wim M. De Borggraeve, Joachim Demaerel
Summary: Sulfur(VI) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction for assembling functional molecules quickly and modularly. This study demonstrated the generation of trifluoromethanesulfonyl fluoride (CF3SO2F) gas in a two chamber system, and its use in the efficient synthesis of triflates and triflamides, with potential applications in peptide modification or coupling reactions. Additionally, redesigning the S-VI-F connector to furnish triflimidoyl fluorides as SuFEx electrophiles allowed for the synthesis of rarely reported triflimidate esters, with H2O identified as a key factor in achieving chemoselective trifluoromethanesulfonation of phenols versus amine groups.
Article
Chemistry, Medicinal
Roeland Vanhoutte, Steven H. L. Verhelst
Summary: In this study, a library of potent and cell-permeable probes for human APT1/2 was successfully created using solid-phase synthesis. The inhibition of APT1/2 in cells was found to have no effect on steady-state levels of protein palmitoylation, indicating that substrates hydrolyzed by APT1/2 can also be hydrolyzed by other protein depalmitoylases.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Jan Pascal Kahler, Vincenzo Davide Aloi, Julia Miedes Aliaga, Sara Kerselaers, Thomas Voets, Joris Vriens, Steven H. L. Verhelst, Marta Barniol-Xicota
Summary: TRPM3 is an ion channel expressed in nociceptive neurons and involved in pain perception. The antifungal compound clotrimazole (Clt) enhances TRPM3-induced pain by augmenting Ca(2+) signaling and opening a non-canonical pore. This study synthesized and evaluated Clt analogues to gain insights into their structure-activity relationship, identifying a pentafluoro-trityl analogue that acts as a TRPM3 agonist in the absence of the endogenous TRPM3 ligand.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Suyuan Chen, Chunguang Liang, Hongli Li, Weimeng Yu, Michaela Prothiwa, Dominik Kopczynski, Stefan Loroch, Marc Fransen, Steven H. L. Verhelst
Summary: We report a full on-resin synthesis of clickable photoaffinity labeling (PAL) probes based on pepstatin, a natural product inhibitor, incorporating a minimal diazirine reactive group. The most effective probes sensitively detect cathepsin D, a biomarker for breast cancer, in cell lysates. Furthermore, through chemical proteomics experiments and deep learning algorithms, we identified sequestosome-1 as a direct interaction partner and substrate of cathepsin D.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Bing-Yu Li, Kexin Su, Luc Van Meervelt, Steven H. L. Verhelst, Ermal Ismalaj, Wim M. De Borggraeve, Joachim Demaerel
Summary: SuFEx chemistry enables rapid and flexible assembly of linkages around a S-VI core by replacing fluoride at an electrophilic sulfur(VI). Thiazyl trifluoride (NSF3) gas is introduced as an excellent parent compound and SuFEx hub to efficiently synthesize mono- and disubstituted fluorothiazynes. These results provide valuable insights into the versatility of these understudied sulfur functionalities, paving the way for future applications.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Jian Yang, Dimitris Korovesis, Shanping Ji, Jan Pascal Kahler, Roeland Vanhoutte, Steven H. L. Verhelst
Summary: In this paper, a short and high-yielding route towards an FP-alkyne derivative is reported, which can be used for bioorthogonal 2-step detection of serine hydrolases. Additionally, red- and green-fluorescent FP-probes were constructed and applied in dual colour labelling of whole proteomes, showing potential for novel applications within ABPP.
ISRAEL JOURNAL OF CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Marine Houdou, Nathalie Jacobs, Jonathan Coene, Mujahid Azfar, Roeland Vanhoutte, Chris van den Haute, Jan Eggermont, Veronique Daniels, Steven H. L. Verhelst, Peter Vangheluwe
Summary: Cells acquire polyamines PUT, SPD, and SPM through polyamine uptake and synthesis pathways, with ATP13A2 and ATP13A3 playing major roles in mammalian polyamine uptake. Biochemical evidence shows that fluorescently labeled polyamines are substrates of ATP13A2 and can be used to measure polyamine uptake. ATP13A3 enables faster and stronger cellular polyamine uptake compared to ATP13A2. Different strategies and fluorophores are used to compare the uptake of new analogs, and it is found that ATP13A2 promotes the uptake of various SPD and SPM analogs, while ATP13A3 mainly stimulates the uptake of PUT and SPD conjugates. P-5B-type ATPase isoforms transport fluorescently labeled polyamine analogs with distinct structure-activity relationship (SAR), suggesting the possibility of designing isoform-specific polyamine probes.
Article
Chemistry, Multidisciplinary
Dimitris Korovesis, Vanessa P. Gaspar, Hester A. Beard, Suyuan Chen, Rene P. Zahedi, Steven H. L. Verhelst
Summary: Photoaffinity labeling followed by tandem mass spectrometry is a commonly used strategy to identify protein targets and drug binding sites. However, it becomes challenging to identify distinct binding sites for bioactive peptides due to complex fragmentation patterns during tandem mass spectrometry. This study presents the development and application of small cleavable photoaffinity reagents that enable light-induced covalent binding and the identification of drug binding sites in bioactive peptides.
Article
Chemistry, Organic
Shanping Ji, Steven H. L. Verhelst
Summary: This article reports a series of novel activity-based probes (ABPs) for targeting the serine protease furin using phosphonate and phosphinate esters as reactive electrophiles. The probes are shown to covalently label furin and exhibit nanomolar potencies, likely due to interactions with different recognition pockets around the active site of furin.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Sandra Codony, Jose M. Entrena, Carla Calvo-Tusell, Beatrice Jora, Rafael Gonzalez-Cano, Silvia Osuna, Ruben Corpas, Christophe Morisseau, Belen Perez, Marta Barniol-Xicota, Christian Grinan-Ferre, Concepcion Perez, Maria Isabel Rodriguez-Franco, Anton L. Martinez, M. Isabel Loza, Merce Pallas, Steven H. L. Verhelst, Coral Sanfeliu, Ferran Feixas, Bruce D. Hammock, Jose Brea, Enrique J. Cobos, Santiago Vazquez
Summary: A new benzohomoadamantane-based sEH inhibitor has been developed to improve the drug metabolism and pharmacokinetics properties for pain-related disorders, showing anti-allodynic and analgesic effects in murine models of capsaicin-induced allodynia and cyclophosphamide-induced cystitis.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Correction
Chemistry, Multidisciplinary
Bing-Yu Li, Lauren Voets, Ruben Van Lommel, Fien Hoppenbrouwers, Mercedes Alonso, Steven H. L. Verhelst, Wim M. De Borggraeve, Joachim Demaerel