Article
Chemistry, Medicinal
Yang Liu, Hanying Ruan, Ying Li, Guoliang Sun, Xiao Liu, Wenhui He, Fengfeng Mao, Miaomiao He, Liwei Yan, Guocai Zhong, Huan Yan, Wenhui Li, Zhiyuan Zhang
Summary: The analogue 27A, derived from natural cyclosporine A, shows potent inhibition of HBV/HDV infection by blocking viral engagement to NTCP, without immunosuppressive activity. It serves as a promising lead for novel anti-HDV/HBV agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Dariusz Zakrzewicz, Joachim Geyer
Summary: Na+/taurocholate cotransporting polypeptide (NTCP) is a transporter involved in the uptake of bile salts and also serves as a receptor for hepatitis B (HBV) and hepatitis D (HDV) viruses. This review highlights recent discoveries on the interactions between NTCP and cofactors relevant to viral entry, and discusses strategies to block these interactions to prevent HBV/HDV infection.
BIOLOGICAL CHEMISTRY
(2023)
Article
Virology
Dariusz Zakrzewicz, Regina Leidolf, Sebastian Kunz, Simon Franz Mueller, Anita Neubauer, Silke Leiting, Nora Goldmann, Felix Lehmann, Dieter Glebe, Joachim Geyer
Summary: Tyrosine 146 and to some extent tyrosine 141 of human NTCP play an essential role in the interaction of HBV with its receptor NTCP and the process of virus entry into hepatocytes.
Article
Virology
Michael Kirstgen, Kira Alessandra Alicia Theresa Lowjaga, Simon Franz Mueller, Nora Goldmann, Felix Lehmann, Dieter Glebe, Karl-Heinz Baringhaus, Joachim Geyer
Summary: This study identified virus-selective inhibitors of NTCP for HBV/HDV through screening different compounds, providing a novel approach for the development of cell-entry inhibitors.
Article
Gastroenterology & Hepatology
Kira A. A. T. Lowjaga, Michael Kirstgen, Simon F. Muller, Nora Goldmann, Felix Lehmann, Dieter Glebe, Joachim Geyer
Summary: The study demonstrates that TLC can rapidly accumulate in NTCP-expressing cells, leading to a long-lasting trans-inhibition of NTCP's transporter and receptor function. This suggests a potential novel target site for pharmacological long-acting HBV/HDV entry inhibitors.
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
(2021)
Article
Virology
Massimo Palatini, Simon Franz Mueller, Michael Kirstgen, Silke Leiting, Felix Lehmann, Lena Soppa, Nora Goldmann, Christin Mueller, Kira Alessandra Alicia Theresa Lowjaga, Jorg Alber, Giuliano Ciarimboli, John Ziebuhr, Dieter Glebe, Joachim Geyer
Summary: This study identified IFITM3 as a novel protein-protein interaction partner of NTCP, which significantly affects the infection of HBV and HDV in hepatoma cells and primary human hepatocytes expressing NTCP. However, the specific mechanism by which this interaction facilitates the infection process remains unknown.
Review
Biochemistry & Molecular Biology
Yan Li, Jun Zhou, Tianliang Li
Summary: Hepatitis B virus (HBV) is a globally prevalent human DNA virus causing chronic liver infection, with the transmembrane protein NTCP identified as the receptor for cellular entry of HBV. Various cell culture and animal models have been established for studying HBV biology and developing treatments for infection. Understanding the NTCP biology could contribute to the design of new therapeutic drugs for preventing liver cell infection.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Virology
Kento Fukano, Mizuki Oshima, Senko Tsukuda, Hideki Aizaki, Mio Ohki, Sam-Yong Park, Takaji Wakita, Kousho Wakae, Koichi Watashi, Masamichi Muramatsu
Summary: NTCP oligomerization plays a crucial role in HBV internalization, and troglitazone inhibits HBV infection by interfering with NTCP oligomerization. Phenylalanine 274 of NTCP is identified as essential for oligomerization. NTCP oligomerization is initiated downstream of the NTCP-EGFR interaction and triggers HBV internalization. This study provides valuable insights into the mechanism of HBV entry and suggests that targeting NTCP oligomerization could be a potential strategy for drug development.
JOURNAL OF VIROLOGY
(2021)
Article
Gastroenterology & Hepatology
Amanda Garrido, Eunjeong Kim, Ana Teijeiro, Paula Sanchez Sanchez, Rosa Gallo, Ajay Nair, Maria Matamala Montoya, Cristian Perna, Guillermo P Vicent, Javier Munoz, Ramon Campos-Olivas, Johannes C. Melms, Benjamin Izar, Robert F. Schwabe, Nabil Djouder
Summary: This study reveals the critical role of MCRS1 in the pathogenesis of cirrhosis, shedding light on potential new treatment strategies for the disease.
JOURNAL OF HEPATOLOGY
(2022)
Article
Gastroenterology & Hepatology
Kiyoaki Ito, Akinori Okumura, Junko S. Takeuchi, Koichi Watashi, Rieko Inoue, Taeko Yamauchi, Kazumasa Sakamoto, Yukiko Yamashita, Yusuke Iguchi, Mizuho Une, Takaji Wakita, Kazuo Umezawa, Masashi Yoneda
Summary: This study investigated inhibitory effects of bile acid (BA) derivatives on HBV infection, highlighting the strong inhibitory effect of INT-767, possibly achieved through inhibiting HBV entry and stimulating FXR signaling. In a chimeric mouse model with humanized liver, INT-767 significantly delayed the rise of HBV markers.
Article
Medicine, General & Internal
Zeyu Sun, Chenjie Huang, Yixian Shi, Rusha Wang, Jun Fan, Ye Yu, Zhehua Zhang, Kundan Zhu, Minwei Li, Qin Ni, Zhi Chen, Min Zheng, Zhenggang Yang
Summary: Hepatitis B virus can influence the host bile acids metabolic pathway during infection, leading to higher levels of conjugated and primary bile acids in patients with chronic infection. The study also revealed differences in hepatic gene expression and gut microbiome diversity between patients with chronic hepatitis B and healthy controls. This new insight may contribute to the development of novel clinical strategies for managing chronic HBV infection.
FRONTIERS IN MEDICINE
(2021)
Review
Chemistry, Medicinal
Zhen-Xi Niu, Peng Nie, Piet Herdewijn, Ya-Tao Wang
Summary: This review provides a comprehensive overview of synthetic routes to antiviral agents used in the management of hepatitis, elucidating the mechanisms of action, clinical applications, and potential research directions. It contributes to improved patient outcomes and reduced global disease burden.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Maya Shofa, Akiho Ohkawa, Yasuyuki Kaneko, Akatsuki Saito
Summary: Domestic cat hepadnavirus (DCH), a novel hepadnavirus in cats, is genetically close to hepatitis B virus (HBV). DCH infection is associated with chronic hepatitis in cats, suggesting its potential as a novel animal model for HBV research. The study also suggests that DCH and HBV may share cell entry molecules, indicating the possibility of interspecies transmission.
ANTIVIRAL RESEARCH
(2023)
Article
Multidisciplinary Sciences
Piyanoot Thongsri, Yongyut Pewkliang, Suparerk Borwornpinyo, Adisak Wongkajornsilp, Suradej Hongeng, Khanit Sa-ngiamsuntorn
Summary: Studies have shown that curcumin (CCM) can reduce HBV infection by inhibiting HBV entry, with its interaction with NTCP playing a key role in this process. Further experiments confirmed the binding affinity between CCM and NTCP, validating the mechanism of CCM inhibition of HBV entry.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Maria Angela Oliva, Carlota Tosat-Bitrian, Lucia Barrado-Gil, Francesca Bonato, Inmaculada Galindo, Urtzi Garaigorta, Beatriz Alvarez-Bernad, Rebeca Paris-Ogayar, Daniel Lucena-Agell, Juan Francisco Gimenez-Abian, Isabel Garcia-Dorival, Jesus Urquiza, Pablo Gastaminza, Jose Fernando Diaz, Valle Palomo, Covadonga Alonso
Summary: Microtubule targeting agents have potential in antiviral drug research, and some clinically used drugs have shown significant inhibitory effects on viral infections. However, their mechanism of action is complex and the relationship with intracellular transport is unclear.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Gastroenterology & Hepatology
Willemien van Zwol, Antoine Rimbert, Justina C. Wolters, Marieke Smit, Vincent W. Bloks, Niels J. Kloosterhuis, Nicolette C. A. Huijkman, Mirjam H. Koster, Umesh Tharehalli, Simon M. de Neck, Colin Bournez, Marceline M. Fuh, Jeroen Kuipers, Sujith Rajan, Alain de Bruin, Henry N. Ginsberg, Gerard J. P. van Westen, M. Mahmood Hussain, Ludger Scheja, Joerg Heeren, Philip Zimmerman, Bart van de Sluis, Jan Albert Kuivenhoven
Summary: By analyzing the co-expression of genes, we identified the small leucine-rich protein 1 (SMLR1) as a player in the VLDL biogenesis pathway. The loss of hepatic SMLR1 in mice leads to hepatic steatosis, reduced VLDL secretion, providing protection against hyperlipidemia and atherosclerosis.
Article
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
Summary: CCR2, a G protein-coupled receptor, is involved in various cancer-related processes. Mutations in CCR2 were investigated for their impact on receptor functionality and antagonist binding. Most mutants showed a decrease in G protein activation in response to the main ligand, while orthosteric antagonist binding was affected by specific mutations and allosteric antagonist binding was completely abolished in certain mutants. Considering CCR2 as a potential drug target in cancer, the negative effects of these mutations on receptor functionality and drug development should be considered.
BIOCHEMICAL PHARMACOLOGY
(2023)
Correction
Pharmacology & Pharmacy
L. S. den Hollander, O. J. M. Bequignon, X. Wang, K. van Wezel, J. Broekhuis, M. Gorostiola Gonzalez, K. E. de Visser, A. P. IJzerman, G. J. P. van Westen, L. H. Heitman
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sohvi Luukkonen, Helle W. van den Maagdenberg, Michael T. M. Emmerich, Gerard J. P. van Westen
Summary: The factors determining a drug's success are diverse, making drug design a multi-objective optimisation problem. With the emergence of machine learning and optimisation methods, there has been a rapid increase in developments and applications in the field of multi-objective compound design. Population-based metaheuristics and deep reinforcement learning are commonly used methods, but conditional learning methods are gaining popularity. This article provides a brief overview of the field and the latest innovations.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Martin Sicho, Sohvi Luukkonen, Helle W. van den Maagdenberg, Linde Schoenmaker, Olivier J. M. Bequignon, Gerard J. P. van Westen
Summary: The discovery of new molecules with desirable properties is a classic challenge in medicinal chemistry. Machine learning has greatly advanced de novo drug design tools, but there is a lack of user-friendly and customizable resources. In this application note, we present DrugEx, a versatile open-source software package for multiobjective reinforcement learning. It includes multiple generator architectures, scoring tools, and optimization methods, and can be used via command line interface or graphical user interface GenUI. The DrugEx package is publicly available at https://github.com/CDDLeiden/DrugEx.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Sohvi Luukkonen, Erik Meijer, Giovanni A. Tricarico, Johan Hofmans, Pieter F. W. Stouten, Gerard J. P. van Westen, Eelke B. Lenselink
Summary: Protein kinases are a protein family with important roles in complex diseases. They have ATP binding sites that can be targeted to create multitarget drugs. Multitask deep learning models outperform single-task deep learning and tree-based models for protein kinase activity prediction.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: In this study, a computational screening pipeline was developed to find new inhibitors for the NET protein. A data-driven approach was used to diversify the chemical space and select optimal proteins to model for NETs. A proteochemometric model was created and applied to an extensive compound database, resulting in the identification of five potential hit compounds with promising inhibitory potencies toward NET.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Xuhan Liu, Kai Ye, Herman W. T. van Vlijmen, Adriaan P. IJzerman, Gerard J. P. van Westen
Summary: In the field of rational drug design, deep learning methods have been employed to generate reliable drug molecules based on new design principles. The Transformer model is used to generate molecular structures, resulting in more effective drug design. The method allows users to design drug molecules according to their specific needs.
JOURNAL OF CHEMINFORMATICS
(2023)
Article
Infectious Diseases
Colin Bournez, Martijn Riool, Leonie de Boer, Robert A. Cordfunke, Leonie de Best, Remko van Leeuwen, Jan Wouter Drijfhout, Sebastian A. J. Zaat, Gerard J. P. van Westen
Summary: To combat infection, host organisms possess defense peptides, including antimicrobial peptides (AMPs), which can target a wide range of pathogenic microorganisms. Researchers have developed a machine learning model called CalcAMP that can predict the activity of AMPs. This model can help in identifying potential short AMPs quickly, which can be an effective solution to the growing issue of multi-drug resistance. CalcAMP is based on a new data set constructed from available public data on AMPs and experimental antimicrobial activities, and it can predict activity against both Gram-positive and Gram-negative bacteria.
Review
Engineering, Multidisciplinary
Joanne M. Donkers, Jamie I. van der Vaart, Evita van de Steeg
Summary: The gut is important for drug absorption and metabolism, and understanding intestinal disease processes is gaining attention. Gut-on-a-chip (GOC) systems offer more translational value compared to conventional models, and various GOC models have been developed. This article reflects on the factors that influence GOC design and presents examples of GOC studies in preclinical drug development and intestinal disease research.
Article
Chemistry, Medicinal
Bert L. H. Beerkens, Inge M. Snijders, Joep Snoeck, Rongfang Liu, Anton T. J. Tool, Sylvia E. Le Devedec, Willem Jespers, Taco W. Kuijpers, Gerard J. P. van Westen, Laura H. Heitman, Adriaan P. IJzerman, Daan van der Es
Summary: This article describes the development of a new probe for detecting human A(3)AR, which has been validated through radioligand displacement, SDS-PAGE, confocal microscopy, and flow cytometry experiments. The probe is expected to be of great significance for future studies on the expression and function of A(3)AR in pathologies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Brandon J. Bongers, Huub J. Sijben, Peter B. R. Hartog, Andrey Tarnovskiy, Adriaan P. IJzerman, Laura H. Heitman, Gerard J. P. van Westen
Summary: This study developed a computational screening pipeline to identify new inhibitors for the high-affinity norepinephrine transporter (NET). By using the chemical space of related proteins, a data-driven approach was used to diversify the known chemical space for NET modeling. The final model, created through a two-step approach, predicted 46 chemically diverse candidates, of which five compounds showed promising inhibitory potency towards NET in experimental assays.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Gastroenterology & Hepatology
Roni F. Kunst, Dirk R. de Waart, Frank Wolters, Suzanne Duijst, Esther W. Vogels, Isabelle Bolt, Joanne Verheij, Ulrich Beuers, Ronald P. J. Oude Elferink, Stan F. J. van de Graaf
Summary: This study demonstrates that reducing the bile salt pool size effectively lowers cholestatic liver injury in mice. Systemic ASBT inhibition may be a valuable treatment for cholestatic liver disease by decreasing the pool size and increasing renal bile salt output, even under conditions of minimal fecal bile salt secretion.