Article
Biochemistry & Molecular Biology
Nina Geiger, Viktoria Diesendorf, Valeria Roll, Eva-Maria Koenig, Helena Obernolte, Katherina Sewald, Julian Breidenbach, Thanigaimalai Pillaiyar, Michael Guetschow, Christa E. Mueller, Jochen Bodem
Summary: Recently, we investigated novel pyridyl indole esters and peptidomimetics as potent inhibitors of SARS-CoV-2 main protease. We analyzed the impact of these compounds on viral replication and found that their effectiveness varied in different cell lines. In Huh-7 cells, the protease inhibitors suppressed viral replication by up to 5 orders of magnitude, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates showed antiviral activity in all cell lines and also in human precision-cut lung slices.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Gangan Yan, Dongsheng Li, Yuan Lin, Zhenghao Fu, Haiyan Qi, Xiaoping Liu, Jing Zhang, Shuyi Si, Yunyu Chen
Summary: A novel screening method was developed in this study, successfully identifying the candidate drug dieckol from a natural product library targeting SARS-CoV-2 Mpro, and demonstrating its competitive inhibitory activity in vitro.
CELL AND BIOSCIENCE
(2021)
Article
Chemistry, Medicinal
Anthi Petrou, Athina Geronikaki, Victor Kartsev, Antonios Kousaxidis, Aliki Papadimitriou-Tsantarliotou, Marina Kostic, Marija Ivanov, Marina Sokovic, Ioannis Nicolaou, Ioannis S. Vizirianakis
Summary: In this study, the antimicrobial activity of seventeen new derivatives was evaluated. The compounds exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, surpassing the activity of ampicillin and streptomycin by 10-50 fold. The most sensitive bacterium was En. Cloacae, while E. coli and M. flavus were the most resistant ones. Compound 8 was found to be the most potent, and exhibited excellent antifungal activity. Docking studies revealed that the antibacterial activity was likely due to the inhibition of E. coli MurB, while the antifungal mechanism involved inhibition of 14a-lanosterol demethylase of CYP51Ca. Drug-likeness and ADMET profile prediction were also performed, and cytotoxicity studies against normal MRC5 cells were conducted for the most active compounds.
Article
Chemistry, Physical
Aditya K. Padhi, Timir Tripathi
Summary: Dimerization of SARS-CoV-2 main protease is essential for its activity, and mutations in the dimeric interface may further stabilize it. Through protein design strategies, potential mutations that can stabilize the protein have been identified in the circulating SARS-CoV-2 genomes, providing insights into viral adaptation and mutational surveillance.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Biochemistry & Molecular Biology
Hussin A. Rothan, Teow Chong Teoh
Summary: The emergence of SARS-CoV-2 has impacted global public health, prompting innovative strategies for antiviral drug development. The identification of variants has made antiviral drug screening more attractive. A successful cell-based assay protocol was designed and validated for screening antiviral drug inhibitors against SARS-CoV-2, leading to the discovery of a new class of viral protease inhibitors.
MOLECULAR BIOTECHNOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Mohammad Azam Ansari, Muhammad Taha, Nizam Uddin, Fazal Rahim, Qazi Mohammad Sajid Jamal, Mohammad N. Alomary, Fahad M. Alshabrmi, Ahmad Almatroudi, Banan Atwah, Zain Alhindi, Naveed Iqbal, Khalid Mohammed Khan
Summary: In this study, a series of indole-based-oxadiazole compounds were successfully synthesized and their structures were characterized. The synthesized compounds exhibited broad-spectrum antibacterial activity and inhibitory effects on biofilm formation against MDR-PA and MRSA. Molecular docking analysis revealed their potential inhibitory activity against both bacteria and the main protease of SARS-CoV-2. The toxicity of the compounds was found to be low. These findings suggest that the synthesized compounds could be useful for preventing and treating biofilm-related microbial infections as well as SARS-CoV-2 infections.
JOURNAL OF SAUDI CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Venkatramanan Varadharajan, Gokulakrishnan Sivasundari Arumugam, Sethupathi Shanmugam
Summary: This study screened potential SARS-CoV-2 Mpro inhibitors from existing literature on isatin derivatives, ultimately selecting 4 compounds with good ADMET properties and binding energies as lead candidates for further experimental validation and development.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Crystallography
Omur Guven, Mehmet Gul, Esra Ayan, J. Austin Johnson, Baris Cakilkaya, Gozde Usta, Fatma Betul Ertem, Nurettin Tokay, Busra Yuksel, Oktay Gocenler, Cengizhan Buyukdag, Sabine Botha, Gihan Ketawala, Zhen Su, Brandon Hayes, Frederic Poitevin, Alexander Batyuk, Chun Hong Yoon, Christopher Kupitz, Serdar Durdagi, Raymond G. Sierra, Hasan DeMirci
Summary: Global investigation into COVID-19 since early 2020 aiming to characterize the virus and develop vaccines. Drug repurposing studies conducted with a focus on in silico drug screening for efficiency. Utilization of advanced technology for high-throughput drug screening with X-ray Free-Electron Laser (XFEL) for remote data collection at ambient temperature.
Article
Chemistry, Physical
Xinyu Qi, Binglin Li, Alejandra B. Omarini, Martin Gand, Xiaoli Zhang, Jiao Wang
Summary: This article investigates the inhibitory activity of 465 promising candidates from 116 traditional Chinese medicines against the main protease of SARS-CoV-2 through molecular docking, dynamic simulation, and drug-likeness analysis. The results show that plant extracts from Forsythiae Fructus, Radix Puerariae, Radix astragali, and Anemarrhenae Rhizoma have high inhibitory efficiencies.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Biochemical Research Methods
Julien Ihssen, Greta Faccio, Chunyan Yao, Teja Sirec, Urs Spitz
Summary: This protocol outlines an in vitro fluorogenic assay for measuring the proteolytic activity of Mpro and identifying inhibitors, with the advantages of high sensitivity, specificity, and easy detectable fluorescent read-out for high throughput screening of new Mpro inhibitors.
Article
Biochemistry & Molecular Biology
Pedro Valada, Sonja Hinz, Christin Vielmuth, Catia R. Lopes, Rodrigo A. Cunha, Christa E. Mueller, Joao Pedro Lopes
Summary: Inosine has neuroprotective effects by indirectly modifying the activity of adenosine receptors and controlling synaptic transmission and plasticity. It acts as a ligand of adenosine receptors with low affinity and shows higher affinity towards the rat A(3) receptor. The impact of inosine on synaptic transmission and plasticity is mediated by modification of extracellular levels of adenosine through equilibrative nucleoside transporters.
PURINERGIC SIGNALLING
(2023)
Article
Pharmacology & Pharmacy
Jan H. Voss, Haneen Al-Hroub, Robin Gedschold, Jennifer M. Dietrich, Evelyn Gaffal, Marieta Toma, Stefan Kehraus, Gabriele M. Koenig, Peter Brust, Bernd K. Fleischmann, Daniela Wenzel, Winnie Deuther-Conrad, Christa E. Mueller
Summary: G protein is identified as a potential drug target for treating complex diseases. The development of specific radiotracers allows for disease diagnosis and research.
Article
Biochemistry & Molecular Biology
Chunyang Bi, Laura Schaekel, Salahuddin Mirza, Katharina Sylvester, Julie Pelletier, Sang -Yong Lee, Thanigaimalai Pillaiyar, Jean Sevigny, Christa E. Mueller
Summary: Ticlopidine is an antithrombotic prodrug that inhibits platelet function by covalently blocking the P2Y12 receptor on thrombocytes. It was found that Ticlopidine also inhibits CD39, an enzyme involved in ATP hydrolysis. In this study, a comprehensive analysis of Ticlopidine derivatives was conducted, leading to the discovery of benzotetrahydropyridines as a novel class of allosteric CD39 inhibitors.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Daniela Brenner, Nina Geiger, Jan Schlegel, Viktoria Diesendorf, Louise Kersting, Julian Fink, Linda Stelz, Sibylle Schneider-Schaulies, Markus Sauer, Jochen Bodem, Juergen Seibel
Summary: Recently, the effectiveness of C6-ceramides in suppressing viral replication by trapping the virus in lysosomes has been demonstrated. In this study, a synthetic ceramide derivative called AKS461 was evaluated for its antiviral activity against SARS-CoV-2. The results showed that AKS461 accumulated in lysosomes and efficiently inhibited SARS-CoV-2 replication in different cell types. This study highlights the importance of lysosomes as the central organelle for C6-ceramides to inhibit viral replication and provides a tool for studying ceramide-associated cellular and viral pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Malgorzata Frankowska, Karolina Wydra, Agata Suder, Magdalena Zaniewska, Dawid Gawlinski, Joanna Miszkiel, Anna Furgala-Wojas, Kinga Salat, Malgorzata Filip, Christa E. Mueller, Katarzyna Kiec-Kononowicz, Magdalena Kotanska
Summary: This study discovered three novel selective ligands for GPR18, including one agonist and two antagonists. The activation of GPR18 has similar effects to the CB receptor system, impacting emotional behavior, food intake, and pain activity. Therefore, GPR18 represents a potential therapeutic target for mood, pain, and/or eating disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Yuta Tsukamoto, Takahiro Hiono, Shintaro Yamada, Keita Matsuno, Aileen Faist, Tobias Claff, Jianyu Hou, Vigneshwaran Namasivayam, Anja vom Hemdt, Satoko Sugimoto, Jin Ying Ng, Maria H. Christensen, Yonas M. Tesfamariam, Steven Wolter, Stefan Juranek, Thomas Zillinger, Stefan Bauer, Takatsugu Hirokawa, Florian I. Schmidt, Georg Kochs, Masayuki Shimojima, Yi-Shuian Huang, Andreas Pichlmair, Beate M. Kuemmerer, Yoshihiro Sakoda, Martin Schlee, Linda Brunotte, Christa E. Mueller, Manabu Igarashi, Hiroki Kato
Summary: Scientists have discovered the importance of host RNA modification in the initiation of influenza virus replication. They found that a derivative of a natural product called TFMT can inhibit this modification and restrict influenza virus replication. TFMT acts synergistically with approved anti-influenza drugs.
Article
Chemistry, Multidisciplinary
Tobias Claff, Jonathan G. Schlegel, Jan H. Voss, Victoria J. Vaassen, Renato H. Weisse, Robert K. Y. Cheng, Sandra Markovic-Mueller, Denis Bucher, Norbert Straeter, Christa E. Mueller
Summary: The authors report the crystal structures of A(2A)AR in complex with Etrumadenant, revealing a previously unknown interaction. These findings have implications for the design of selective receptor antagonists.
COMMUNICATIONS CHEMISTRY
(2023)
Editorial Material
Chemistry, Medicinal
Jeffrey Aube, Craig W. Lindsley, Christa E. Mueller
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Nina Geiger, Viktoria Diesendorf, Valeria Roll, Eva-Maria Koenig, Helena Obernolte, Katherina Sewald, Julian Breidenbach, Thanigaimalai Pillaiyar, Michael Guetschow, Christa E. Mueller, Jochen Bodem
Summary: Recently, we investigated novel pyridyl indole esters and peptidomimetics as potent inhibitors of SARS-CoV-2 main protease. We analyzed the impact of these compounds on viral replication and found that their effectiveness varied in different cell lines. In Huh-7 cells, the protease inhibitors suppressed viral replication by up to 5 orders of magnitude, while in Calu-3 cells, suppression by 2 orders of magnitude was achieved. Three pyridin-3-yl indole-carboxylates showed antiviral activity in all cell lines and also in human precision-cut lung slices.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Daniel Marx, Mohamed Wessam Alnouri, Sophie Clemens, Robin Gedschold, Yvonne Riedel, Ghazl Al Hamwi, Thanigaimalai Pillaiyar, Jorg Hockemeyer, Vigneshwaran Namasivayam, Christa E. Mueller
Summary: This study discovered a xanthine derivative that activates the main variant of MRGPRX4, and optimization resulted in analogs with high potency and metabolic stability. These compounds are promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Sven Marcel Stefan, Jens Pahnke, Vigneshwaran Namasivayam
Summary: The discovery of distinctive lead molecules and novel drug targets is crucial for drug discovery, especially for orphan diseases. Huntington's disease is a neurodegenerative orphan disease with well-described pathology but poorly understood pathophysiological background and molecular mechanisms. Only two drugs have been approved for this disease, addressing only symptomatic aspects. Despite the effectiveness of several hundred agents in in vitro and/or in vivo models, successful translation into clinical use is rare.
JOURNAL OF CHEMINFORMATICS
(2023)