Article
Multidisciplinary Sciences
David Bajusz, Warren S. Wade, Grzegorz Satala, Andrzej J. Bojarski, Janez Ilas, Jessica Ebner, Florian Grebien, Henrietta Papp, Ferenc Jakab, Alice Douangamath, Daren Fearon, Frank von Delft, Marion Schuller, Ivan Ahel, Amanda Wakefield, Sandor Vajda, Janos Gerencser, Peter Pallai, Gyoergy M. Keseru
Summary: Fragment-based drug design offers a bottom-up approach for drug development, combining pharmacophores and protein hotspots theory to create a design protocol for fragment libraries named SpotXplorer, demonstrating effectiveness on both established and emerging drug targets.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Jean-Pierre Daguer, Arthur Gonse, Yevhenii Shchukin, Lluc Farrera-Soler, Sofia Barluenga, Nicolas Winssinger
Summary: A dual Bcl-X-L / Bcl-2 inhibitor was discovered from DNA-encoded libraries using a two-step process. The best compound showed comparable cellular activity to venetoclax, the first-in-class therapeutic targeting Bcl-2. Through a series of assays, the compound was found to have tight binding adducts with selective target engagement and high affinity.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Arvind Negi, Anne Sophie Voisin-Chiret
Summary: Apoptosis is a highly regulated cellular process and aberration in apoptosis is common in various disorders. Bcl-x(L) is an antiapoptotic protein associated with survival and chemoresistance in cancer and senescent cells. Various Bcl-x(L) inhibitors have been developed, but they have limitations. New pharmacological approaches such as PROTACs and SNIPERs show promise in improving treatment efficacy.
Review
Biochemistry & Molecular Biology
Anna Maria Luciano, Ana B. Perez-Oliva, Victoriano Mulero, Donatella Del Bufalo
Summary: Apoptosis is crucial for eliminating damaged cells in multicellular organisms. Bcl-xL, an anti-apoptotic protein, plays significant roles in cancer, including melanoma, by regulating cell survival, migration, invasion, and angiogenesis. Targeting Bcl-xL may offer potential benefits for cancer patients, but further studies are needed to develop safe and effective inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Mario Morales-Martinez, Mario I. Vega
Summary: Members of the Bcl-2 family, particularly BCL-xL, play a crucial role in regulating cell apoptosis. Understanding the transcriptional regulation and activities of BCL-xL in hematological malignancies is important for its potential as a biomarker and its clinical relevance. However, its role in cancer may vary depending on the cellular or tissue context.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Gastroenterology & Hepatology
Paula Hoffmeister-Wittmann, Andreas Mock, Federico Nichetti, Felix Korell, Christop E. Heilig, Anna-Lena Scherr, Michael Gunther, Thomas Albrecht, Eblina Kelmendi, Kaiyu Xu, Luisa Nader, Annika Kessler, Nathalie Schmitt, Sarah Fritzsche, Sofia Weiler, Benjamin Sobol, Albrecht Stenzinger, Stefan Boeck, Christoph B. Westphalen, Klaus Schulze-Osthoff, Jorg Trojan, Thomas Kindler, Wilko Weichert, Karsten Spiekermann, Michael Bitzer, Gunnar Folprecht, Anna-Lena Illert, Melanie Boerries, Frederick Klauschen, Sebastian Ochsenreiter, Jens Siveke, Sebastian Bauer, Hanno Glimm, Benedikt Brors, Jennifer Huellein, Daniel Huebschmann, Sebastian Uhrig, Peter Horak, Simon Kreutzfeld, Jesus M. Banales, Christoph Springfeld, Dirk Jaeger, Peter Schirmacher, Stephanie Roessler, Steffen Ormanns, Benjamin Goeppert, Stefan Froehling, Bruno C. Koehler
Summary: The study identified Bcl-x(L) as a key protein in cell death resistance of CCA and suggested its potential prognostic value, serving as a potential therapeutic target.
LIVER INTERNATIONAL
(2022)
Article
Chemistry, Medicinal
Simon Cross, Gabriele Cruciani
Summary: Understanding chemical modifications of known ligands is crucial in structure-based drug design. FragExplorer software helps users find fragments that best match molecular interaction fields in a protein binding site, allowing ligand expansion or replacement. FragExplorer offers fast computation speed and high fragment retrieval rate.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Medicinal
Zhi-Fu Tao, Xilu Wang, Jun Chen, Justin P. Ingram, Sha Jin, Russell A. Judge, Peter J. Kovar, Chang Park, Chaohong Sun, Brian D. Wakefield, Li Zhou, Haichao Zhang, Steven W. Elmore, Darren C. Phillips, Andrew S. Judd, Joel D. Leverson, Andrew J. Souers
Summary: A novel series of selective BCL-X-L inhibitors exemplified by A-1293102, with picomolar binding affinity to BCL-X-L, efficiently and selectively killed BCL-X-L-dependent tumor cells. X-ray crystallographic analysis revealed the key hydrogen bonding network in the P2 binding pocket of BCL-X-L and efficient occupancy of the P4 pocket similar to navitoclax.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Biochemistry & Molecular Biology
Julie Bas, Trang Nguyen, Germain Gillet
Summary: Bcl-2 family proteins, known for their role in regulating apoptosis, also have non-canonical functions in the CNS. Bcl-xL, a close homolog of Bcl-2, plays a crucial role in neuronal development, promoting ATP generation in mitochondria and contributing to synaptic transmission without causing cell death. Understanding the roles of cell death machinery in neurons may have important clinical implications for degenerative diseases and aging.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Anna Maria Luciano, Marta Di Martile, Ana B. Perez-Oliva, Marica Di Caprio, Maria Laura Foddai, Simonetta Buglioni, Victoriano Mulero, Donatella Del Bufalo
Summary: BackgroundMacrophages can evolve during tumor progression and acquire Tumor-Associated Macrophage (TAMs) phenotype. Bcl-xL, a member of the Bcl-2 family, is overexpressed in melanoma and can recruit macrophages and induce a M2 phenotype. This study reveals the important role of Bcl-xL in melanoma.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Cristina Mas-Bargues, Consuelo Borras, Jose Vina
Summary: Cellular senescence is related to the inability of cells to adapt to stress conditions, a specific level of senescence can promote development, remodeling and healing, while chronicity of senescence can result from constant stresses and a weakening immune system. Centenarians overexpress Bcl-xL, which helps them avoid the deleterious effects of accumulated senescent cells and maintain a fully functional immune system. There is a paradox in the fact that Bcl-xL inhibitors have been shown to protect from aging in animal models.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Anh Thi Ngoc Bui, Hyojin Son, Seulki Park, Sohee Oh, Jin-Sik Kim, Jin Hwa Cho, Hye-Jin Hwang, Jeong-Hoon Kim, Gwan-Su Yi, Seung-Wook Chi
Summary: In this study, octenidine was identified as a novel Bcl-xL inhibitor through structural feature-based deep learning and molecular docking. By targeting the anti-apoptotic protein Bcl-xL, octenidine promotes apoptosis in cancer cells, inhibiting their proliferation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Harrison Green, David R. Koes, Jacob D. Durrant
Summary: Machine learning has been increasingly applied in the field of computer-aided drug discovery, showing notable advances in binding-affinity prediction, virtual screening, and QSAR. A deep convolutional neural network was used to predict appropriate fragments based on the structure of a receptor/ligand complex, with an efficiency of about 58% in selecting correct fragments from known ligands. The trained DeepFrag model and its associated software have been released under the Apache License, Version 2.0.
Article
Biochemistry & Molecular Biology
Vivek Tyagi, Victor Vasquez-Montes, J. Alfredo Freites, Alexander Kyrychenko, Douglas J. Tobias, Alexey S. Ladokhin
Summary: The study demonstrates that the protonation state of the protein and the cardiolipin content of the membrane modulate the orientation of membrane-anchored Bcl-xL, affecting the exposure of its BH3-binding groove and thus its interaction with pro-apoptotic proteins.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Ryan Kolb, Umasankar De, Sajid Khan, Yuewan Luo, Myung-Chul Kim, Haijun Yu, Chaoyan Wu, Jiao Mo, Xin Zhang, Peiyi Zhang, Xuan Zhang, Nicholas Borcherding, Daniel Koppel, Yang-Xin Fu, Song Guo Zheng, Dorina Avram, Guangrong Zheng, Daohong Zhou, Weizhou Zhang
Summary: The pharmacological degradation of BCL-X-L preferentially induces apoptosis of tumor-infiltrating Tregs, promoting CD8 T cell activation and effective suppression of tumor growth without causing damage to normal tissues or thrombocytopenia. This finding suggests that targeting BCL-X-L could be a potential therapeutic strategy for cancer immunotherapy.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Benoit Bestgen, Isabelle Krimm, Irina Kufareva, Ahmed Ashraf Moustafa Kamal, Wei-Guang Seetoh, Chris Abell, Rolf W. Hartmann, Ruben Abagyan, Claude Cochet, Marc Le Borgne, Matthias Engel, Thierry Lomberget
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Yunqi Li, Yuan He, Ting Shao, Haixiang Pei, Weikai Guo, Dazhao Mi, Isabelle Krimm, Yuanjin Zhang, Peili Wang, Xin Wang, Mingyao Liu, Zhengfang Yi, Yihua Chen
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Review
Chemistry, Medicinal
Claire Raingeval, Isabelle Krimm
FUTURE MEDICINAL CHEMISTRY
(2019)
Article
Multidisciplinary Sciences
Irina Kufareva, Benoit Bestgen, Paul Brear, Renaud Prudent, Beatrice Laudet, Virginie Moucadel, Mohamed Ettaoussi, Celine F. Sautel, Isabelle Krimm, Matthias Engel, Odile Filhol, Marc Le Borgne, Thierry Lomberget, Claude Cochet, Ruben Abagyan
SCIENTIFIC REPORTS
(2019)
Article
Chemistry, Analytical
Lucile Lecas, Lucie Hartmann, Lydia Caro, Sarah Mohamed-Bouteben, Claire Raingeval, Isabelle Krimm, Renaud Wagner, Vincent Dugas, Claire Demesmay
ANALYTICA CHIMICA ACTA
(2020)
Article
Chemistry, Medicinal
Alexandre Bancet, Claire Raingeval, Thierry Lomberget, Marc Le Borgne, Jean-Francois Guichou, Isabelle Krimm
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Nicolas Lebouvier, Fabrice Pagniez, Young Min Na, Da Shi, Patricia Pinson, Mathieu Marchivie, Jean Guillon, Tarek Hakki, Rita Bernhardt, Sook Wah Yee, Claire Simons, Marie-Pierre Leze, Rolf W. Hartmann, Angelique Mularoni, Guillaume Le Baut, Isabelle Krimm, Ruben Abagyan, Patrice Le Pape, Marc Le Borgne
Article
Biochemical Research Methods
Jordane Preto, Isabelle Krimm
Summary: The voltage-dependent anion channel (VDAC) is a critical membrane protein in the mitochondrial outer membrane that regulates ion and ATP transport while playing a key role in apoptosis. The N-terminus of VDAC is an intrinsically disordered region that significantly impacts its gating mechanism, providing new insights into the dynamics of the channel.
PLOS COMPUTATIONAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Veronique Roig-Zamboni, Sarah Barelier, Robert Dixon, Nicola F. Galley, Amani Ghanem, Heloize Cahuzac, Quoc Phong Nguyen, Bartlomiej Salamaga, Peter J. Davis, Yves Bourne, Stephane Mesnage, Florence Vincent
Summary: The cleavage of septal peptidoglycan during cell division helps in separating the daughter cells. The N-acetylglucosaminidase AtlA in Enterococcus faecalis plays a crucial role in cell separation and its mutants show decreased virulence. AtlA has structural homologs in other pathogens, making it a potential target for developing inhibitors of bacterial pathogenesis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Jeremy Caburet, Benjamin Boucherle, Sofiane Bourdillon, Giorgia Simoncelli, Federica Verdirosa, Jean-Denis Docquier, Yohann Moreau, Isabelle Krimm, Serge Crouzy, Marine Peuchmaur
Summary: Hydrolysis of beta-lactam drugs by serine or metallo-beta-lactamases is a major mechanism of antibiotic resistance. New Delhi Metallo-beta-lactamase-1 (NDM-1) is an important target for the development of NDM-1 inhibitors. Using a combination of virtual screening and NMR screening, we identified 37 fragments and synthesized inhibitors with inhibitory activity on NDM-1.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Sarah Barelier, Romain Avellan, Giri Raj Gnawali, Patrick Fourquet, Veronique Roig-Zamboni, Isabelle Poncin, Vanessa Point, Yves Bourne, Stephane Audebert, Luc Camoin, Christopher D. Spilling, Stephane Canaan, Jean-Francois Cavalier, Gerlind Sulzenbacher
Summary: We report the synthesis of new CyC alkyne-containing inhibitors (CyCyne) and their use for the direct fishing of target proteins in M. tb culture via bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP). This approach led to the capture and identification of a variety of enzymes, including HsaD, which is required for the survival of M. tb within macrophages and is a potential therapeutic target. The specificity of HsaD inhibition by the CyC analogues was confirmed through biochemical and structural approaches.
Editorial Material
Biochemistry & Molecular Biology
Sarah Barelier, Gerlind Sulzenbacher
Summary: In this study, Armstrong and his team investigate the structure of human fucosidase FucA1. Their findings not only resolve the debate on the enzyme's catalytic mechanism but also offer a valuable structural template for the design of drugs to treat fucosidosis, a rare but severe lysosomal storage disease.
Article
Biochemical Research Methods
Julie Gil, Isabelle Krimm, Vincent Dugas, Claire Demesmay
Summary: In affinity chromatography, non-specific interactions between ligands and the affinity column can cause misinterpretations and lack of specificity. A methodology was proposed to identify the origin of such interactions with the underlying material of the column. By investigating the retention behavior of different compounds, it was found that hydrophobic effects were the main source of non-specific interactions. To reduce these interactions, a new hydrophilic monolith was developed. It showed improved surface properties, higher protein density, and significantly reduced non-specific interactions.
JOURNAL OF CHROMATOGRAPHY A
(2023)
Article
Chemistry, Medicinal
Marcel Hausdorff, Adrien Delpal, Sarah Barelier, Laura Nicollet, Bruno Canard, Franck Touret, Agathe Colmant, Bruno Coutard, Jean-Jacques Vasseur, Etienne Decroly, Francoise Debart
Summary: The COVID-19 pandemic has raised the urgent need for new therapeutic drugs targeting the SARS-CoV-2 replication machinery. This study focuses on the development of inhibitors targeting the highly conserved protein nsp14, which is involved in viral RNA translation and immune evasion. Through structure-guided drug design, 26 novel adenosine mimetics were synthesized, one of which showed selective inhibition of nsp14 N7-MTase activity with high potency against SARS-CoV-2 replication in cell culture.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Claire Raingeval, Olivier Cala, Beatrice Brion, Marc Le Borgne, Roderick Eliot Hubbard, Isabelle Krimm
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2019)