Article
Biochemistry & Molecular Biology
Meredith N. Frazier, Lucas B. Dillard, Juno M. Krahn, Lalith Perera, Jason G. Williams, Isha M. Wilson, Zachary D. Stewart, Monica C. Pillon, Leesa J. Deterding, Mario J. Borgnia, Robin E. Stanley
Summary: Nsp15 is a uridine specific endoribonuclease used by coronaviruses to cleave viral RNA and evade host immune defense systems. The structure of Nsp15 reveals critical residues involved in substrate specificity, nuclease activity, and oligomerization, providing insights into viral RNA processing and informing the development of new anti-viral therapeutics.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Isha M. Wilson, Meredith N. Frazier, Jian-Liang Li, Thomas A. Randall, Robin E. Stanley
Summary: Global sequencing efforts on SARS-CoV-2 have revealed mutations in the viral protein Nsp15, which affects viral replication and immune evasion. Mutations were found to decrease the enzyme activity and increase the monomeric form of Nsp15. These findings provide insights into the impact of viral variants on virus evolution and drug design.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Microbiology
Yunfei Xie, Chener Chen, Ding Zhang, Zhe Jiao, Yixi Chen, Gang Wang, Yubei Tan, Wanpo Zhang, Shaobo Xiao, Guiqing Peng, Yuejun Shi
Summary: This study verifies the importance of the active sites of EndoU in coronaviruses and finds that nsp15 antagonizes interferon response through its EndoU activity. However, compared to wild-type viruses, the propagation and pathogenicity of the EndoU-deficient viruses in immunocompetent cells remain unchanged.
MICROBIOLOGY SPECTRUM
(2023)
Article
Biochemistry & Molecular Biology
Andre Schutzer Godoy, Aline Minalli Nakamura, Alice Douangamath, Yun Song, Gabriela Dias Noske, Victor Oliveira Gawriljuk, Rafaela Sachetto Fernandes, Humberto D. Muniz Pereira, Ketllyn Irene Zagato Oliveira, Daren Fearon, Alexandre Dias, Tobias Krojer, Michael Fairhead, Alisa Powell, Louise Dunnet, Jose Brandao-Neto, Rachael Skyner, Rod Chalk, David Bajusz, Miklos Bege, Aniko Borbas, Gyoergy Miklos Keseru, Frank von Delft, Glaucius Oliva
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, plays a critical role in the virus's ability to evade the immune system and is a potential target for antiviral drug development. However, the complexity of NendoU's structure and kinetics, as well as the lack of structural complexes, hinder the development of inhibitors.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Berta Canal, Ryo Fujisawa, Allison W. McClure, Tom D. Deegan, Mary Wu, Rachel Ulferts, Florian Weissmann, Lucy S. Drury, Agustina P. Bertolin, Jingkun Zeng, Rupert Beale, Michael Howell, Karim Labib, John F. X. Diffley
Summary: SARS-CoV-2 encodes 16 non-structural proteins (nsp) with important roles in viral genome replication, transcription and host immune evasion, with nsp15 playing a key role in host immune evasion. Expression and purification of nsp15 recombinant protein has been described, showing evidence of allosteric behavior, and NSC95397 has been identified as an inhibitor of nsp15 endoribonuclease in vitro. Further studies are needed to determine the impact of nsp15 inhibition on host immune evasion.
BIOCHEMICAL JOURNAL
(2021)
Article
Multidisciplinary Sciences
Ryan Choi, Mowei Zhou, Roger Shek, Jesse W. Wilson, Logan Tillery, Justin K. Craig, Indraneel A. Salukhe, Sarah E. Hickson, Neeraj Kumar, Rhema M. James, Garry W. Buchko, Ruilian Wu, Sydney Huff, Tu-Trinh Nguyen, Brett L. Hurst, Sara Cherry, Lynn K. Barrett, Jennifer L. Hyde, Wesley C. Van Voorhis
Summary: Several compounds with inhibitory effects on SARS-CoV-2 nsp15 endonuclease have been identified through high-throughput screening, including Exebryl-1. Despite the inhibitory concentrations of Exebryl-1 exceeding therapeutic levels, further optimization shows promising potential for its use as an antiviral against SARS-CoV-2.
Article
Agriculture, Multidisciplinary
Seokho Hong, Sang Hwan Seo, Sun-Je Woo, Yonghoon Kwon, Manki Song, Nam-Chul Ha
Summary: SARS-CoV-2 and its variants present challenges to vaccine development and treatment. Natural compounds like EGCG, baicalin, and quercetin have been identified as potential inhibitors against the virus, with EGCG showing potent antiviral activity.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Jason K. Perry, Todd C. Appleby, John P. Bilello, Joy Y. Feng, Uli Schmitz, Elizabeth A. Campbell
Summary: The SARS-CoV-2 replication-transcription complex is a hexameric assembly of nonstructural viral proteins centered on nsp15, which recruit various other proteins to perform different functions such as RNA unwinding and mRNA capping. The model provides insights into the intricate processes involved in viral genome replication and mRNA transcription.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Monica C. Pillon, Meredith N. Frazier, Lucas B. Dillard, Jason G. Williams, Seda Kocaman, Juno M. Krahn, Lalith Perera, Cassandra K. Hayne, Jacob Gordon, Zachary D. Stewart, Mack Sobhany, Leesa J. Deterding, Allen L. Hsu, Venkata P. Dandey, Mario J. Borgnia, Robin E. Stanley
Summary: Nsp15 is a uridine specific endoribonuclease present in all coronaviruses. The cryo-EM structures of SARS-CoV-2 Nsp15 in the apo and UTP-bound states, together with biochemical experiments, mass spectrometry, and molecular dynamics simulations, provide insights into the catalytic mechanism of Nsp15 and its conformational dynamics.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Medicinal
Rui Wang, Annelies Stevaert, Tien Nguyen Truong, Qifei Li, Besir Krasniqi, Benjamin Van Loy, Arnout Voet, Lieve Naesens, Wim Dehaen
Summary: The study investigates the structure-activity relationship of novel coronavirus inhibitors and identifies a class of 1,2,3-triazolo fused triterpenoid compounds with strong antiviral activity against HCoV-229E.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Medicinal
Maimoona S. Bhutta, Daniel G. Sausen, Elisa S. Gallo, Harel Dahari, Gustavo F. Doncel, Ronen Borenstein
Summary: Ginkgolic Acid (GA) has shown promising potential as an effective antiviral treatment for Human Coronavirus strain 229E (HCoV-229E) infection, significantly reducing progeny virus production, viral protein expression, and cytopathic effects in human epithelial lung cells (MRC-5).
Review
Biochemistry & Molecular Biology
Adelina Lombrea, Alexandra Denisa Scurtu, Stefana Avram, Ioana Zinuca Pavel, Maris Turks, Jevgenija Luginina, Uldis Peipins, Cristina Adriana Dehelean, Codruta Soica, Corina Danciu
Summary: Clinical trials have shown that natural compounds can be effective in managing cancer, serving as starting points for new drug development. Betulonic acid and its derivatives have potential as anticancer agents, but more research is needed to fully understand their mechanisms and efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Immunology
Ivan N. N. Koshkin, Vasily S. S. Vlasenko, Valentina I. I. Pleshakova, Larisa E. E. Alkhimova, Andrey V. V. Elyshev, Ivan V. V. Kulakov
Summary: This study investigated the morphological changes in the lymphoid tissue associated with the bronchial mucosa lungs (BALT) in a guinea pig model of experimental tuberculosis using conjugates based on BCG antigens with betulin and its derivatives. The results showed a significant decrease in the BALT response and an increase in the number of plasma cells in the lung tissues of guinea pigs treated with these conjugates.
Article
Biochemistry & Molecular Biology
Meredith N. Frazier, Lucas B. Dillard, Juno M. Krahn, Lalith Perera, Jason G. Williams, Isha M. Wilson, Zachary D. Stewart, Monica C. Pillon, Leesa J. Deterding, Mario J. Borgnia, Robin E. Stanley
Summary: Nsp15 is a uridine specific endoribonuclease used by coronaviruses, which cleaves viral RNA and evades host immune defense systems. Studies have revealed its substrate specificity and cleavage preferences.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Gulnara Giniyatullina, Anastasiya Petrova, Akhat G. Mustafin, Zulfia R. Zileeva, Ulyana Sh Kuzmina, Yulia V. Vakhitova, Oxana B. Kazakova
Summary: A series of betulonic acid N-methylpiperazinyl amide derivatives were synthesized and evaluated for their cytotoxic activity against cancer cell lines, with some compounds showing higher activity than the standard drug doxorubicin. Compound 11 was found to promote apoptosis induction, while compound 14 exhibited cytostatic and cytotoxic activity dependent on the cell line. Compounds 11 and 14 are promising for future antitumor drug development.
Article
Biochemistry & Molecular Biology
Saida Lachhab, Az-eddine El Mansouri, Ahmad Mehdi, Indira Dennemont, Johan Neyts, Dirk Jochmans, Graciela Andrei, Robert Snoeck, Yogesh S. Sanghvi, Mustapha Ait Ali, Philippe M. Loiseau, Hassan B. Lazrek
Summary: A new series of 3-acetyl-1,3,4-oxadiazoline hybrid molecules were designed and synthesized, and their activities against pathogens were screened. One of the intermediates exhibited significant antileishmanial activity.
MOLECULAR DIVERSITY
(2023)
Article
Pharmacology & Pharmacy
Winston Chiu, Joost Schepers, Thibault Francken, Laura Vangeel, Kayvan Abbasi, Dirk Jochmans, Steven De Jonghe, Hendrik Jan Thibaut, Volker Thiel, Johan Neyts, Manon Laporte, Pieter Leyssen
Summary: We developed a high-throughput screening method for antiviral drugs against SARS-CoV-2 using a fully automated robot system. This novel dual-reporter virus-cell-based imaging assay proved to be convenient and powerful for screening large compound libraries. The selected host cell subclone showed high expression of the reporter virus, resistance to virus-induced cytopathogenic effects, and strong fluorescent signals, making it suitable for high-throughput screening purposes.
ANTIVIRAL RESEARCH
(2023)
Article
Chemistry, Medicinal
Martina Salerno, Carmine Varricchio, Federica Bevilacqua, Dirk Jochmans, Johan Neyts, Andrea Brancale, Salvatore Ferla, Marcella Bassetto
Summary: Different viruses, such as enterovirus 71, rely on the host enzyme METTL3 to complete their cytoplasmic life cycle stages. By modulating the activity of this enzyme, it is possible to interfere with a broad range of viral infections. In this study, a series of nucleoside analogues were designed as inhibitors of human METTL3 to target multiple viral infections. Through molecular docking studies and synthesis, several novel and potent inhibitors of enterovirus 71 were identified.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Az-Eddine El Mansouri, Saida Lachhab, Ali Oubella, Mehdi Ahmad, Johan Neyts, Dirk Jochmans, Winston Chiu, Laura Vangeel, Steven De Jonghe, Hamid Morjani, Mustapha Ait Ali, Mohamed Zahouily, Yogesh S. Sanghvi, Hassan B. Lazrek
Summary: Analogous to pyrimidine and 1,3,4-oxadiazole, the newly synthesized pyrimidine-1,3,4-oxadiazole conjugated hybrid molecules exhibited potential anticancer activity. Specifically, compound 5e demonstrated significant growth inhibition against various cancer cell lines and induced apoptosis through caspase activation and cell-cycle arrest.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Editorial Material
Microbiology
Dirk Jochmans, Manon Laporte, Johan Neyts
Summary: Broad-spectrum antiviral drugs should be developed and stockpiled during epidemic/pandemic periods for immediate response to new virus outbreaks, and they will continue to be important tools even after the introduction of vaccines and monoclonal antibodies.
CELL HOST & MICROBE
(2023)
Article
Biochemistry & Molecular Biology
Christine Helsen, Maria Santa Rocca, Tien T. Nguyen, Roy Eerlings, Xiao Yin Lee, Sofie De Block, Cinzia Vinanzi, Francesco Di Millo, Vito Giagulli, Arnout Voet, Alberto Ferlin, Frank Claessens
Summary: We discovered the missense mutation V770D in the androgen receptor of two sisters with complete androgen insensitivity. The mutation resulted in transcriptional inactivity and impaired dimerization and ligand binding affinity. We found that the AR LBD dimer structure could be better described by a GR-like LBD dimer model, and the V770 residue played a key role in the stability of this dimer.
Article
Multidisciplinary Sciences
Rana Abdelnabi, Dirk Jochmans, Kim Donckers, Bettina Trueeb, Nadine Ebert, Birgit Weynand, Volker Thiel, Johan Neyts
Summary: The SARS-CoV-2 main protease (3CLpro) is an important target for COVID-19 treatment. A drug-resistant virus (3CLpro(res)) that is cross-resistant with nirmatrelvir has been identified. The 3CLpro(res) virus can replicate efficiently and be transmitted in Syrian hamsters, but nirmatrelvir still exhibits some antiviral activity against this virus.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Sam Balzarini, Roosje Van Ende, Arnout Voet, Koen Geuten
Summary: Despite progress in methodology, a widely applicable, easily scalable, and cost-effective procedure for isolating specific RNPs is still lacking. We present the Silica-based Acidic Phase Separation (SAPS)-capture workflow, which combines previously described techniques in a versatile, optimal, and cost-effective protocol. This method isolates specific RNPs from pre-purified samples, resulting in an increased RNP/bead ratio and reduced experimental cost. Validation experiments were conducted using yeast and Arabidopsis, demonstrating the applicability of this procedure to study the ribonome of any RNA molecule in any organism or tissue type.
SCIENTIFIC REPORTS
(2023)
Article
Pharmacology & Pharmacy
Evelien Vanderlinden, Arnaud Boonen, Sam Noppen, Geert Schoofs, Maya Imbrechts, Nick Geukens, Robert Snoeck, Annelies Stevaert, Lieve Naesens, Graciela Andrei, Dominique Schols
Summary: PRO-2000, a sulfonated polyanionic compound, has anti-SARS-CoV-2 activity by blocking the entry pathway and inhibiting the binding of the S protein to its receptor. It can potentially inhibit a broad range of SARS-CoV-2 variants.
ANTIVIRAL RESEARCH
(2023)
Article
Pharmacology & Pharmacy
Robert Konkel, Aleksandra Milewska, Nguyen Dan Thuc Do, Emilia Barreto Duran, Artur Szczepanski, Jacek Plewka, Ewa Wieczerzak, Sofia Iliakopoulou, Triantafyllos Kaloudis, Dirk Jochmans, Johan Neyts, Krzysztof Pyrc, Hanna Mazur-Marzec
Summary: In this study, fifteen cyanopeptolins (CPs) were isolated from the Baltic cyanobacterium Nostoc edaphicum and tested for their activity against SARS-CoV-2. The results showed that the Arg-containing CP978 exhibited the strongest inhibition of Delta SARS-CoV-2 infection, possibly through direct interaction with the virus. CP978 also showed significant reduction in virus replication in human airway epithelial cells. Among the tested SARS-CoV-2 variants, CP978 had no effect on the Wuhan variant. These findings suggest that CP978 has potential as an antiviral drug candidate.
ANTIVIRAL RESEARCH
(2023)
Article
Chemistry, Medicinal
Rui Wang, Annelies Stevaert, Tien Nguyen Truong, Qifei Li, Besir Krasniqi, Benjamin Van Loy, Arnout Voet, Lieve Naesens, Wim Dehaen
Summary: The study investigates the structure-activity relationship of novel coronavirus inhibitors and identifies a class of 1,2,3-triazolo fused triterpenoid compounds with strong antiviral activity against HCoV-229E.
ARCHIV DER PHARMAZIE
(2023)
Meeting Abstract
Cardiac & Cardiovascular Systems
J. Kaes, E. Vanhulle, L. Seldeslachts, C. Hooft, H. Beeckmans, X. Jin, P. Kerckhof, J. Van Slambrouck, D. Van Raemelonck, G. Vande Velde, L. Naesens, D. Schols, L. J. Ceulemans, R. Vos, K. Vertneire, B. M. Vanaudenaerde
JOURNAL OF HEART AND LUNG TRANSPLANTATION
(2023)