Article
Multidisciplinary Sciences
Joseph A. Newman, Alice Douangamath, Setayesh Yadzani, Yuliana Yosaatmadja, Antony Aimon, Jose Brandao-Neto, Louise Dunnett, Tyler Gorrie-stone, Rachael Skyner, Daren Fearon, Matthieu Schapira, Frank von Delft, Opher Gileadi
Summary: The SARS-CoV-2 NSP13 helicase is crucial for viral replication and is considered a promising drug target. Crystal structures of NSP13 in different forms provide insights into its mechanism and potential inhibition methods. A crystallographic fragment screen identified 65 fragments bound to NSP13, offering opportunities for developing novel antiviral drugs.
NATURE COMMUNICATIONS
(2021)
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
Chemistry, Medicinal
Ashima Chopra, Joseph D. Bauman, Francesc X. Ruiz, Eddy Arnold
Summary: X-ray crystallographic fragment screening (XCFS) utilizes fragment-sized molecules to access binding sites on proteins that may be inaccessible to larger drug-like molecules. This study focused on halogenated fragments, which have been shown to bind to proteins more frequently than non-halogenated fragments. The Halo Library containing 46 halogenated fragments was screened against HIV-1 reverse transcriptase crystals, resulting in the discovery of new binding sites and identification of hot spots. This small library can be a useful tool for quickly assessing target feasibility, mapping hot spots and cryptic sites, and finding fragment binders for drug lead development.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Chao Zhang, Junjie Xiang, Qian Xie, Jing Zhao, Hong Zhang, Erfang Huang, Pangchui Shaw, Xiaoping Liu, Chun Hu
Summary: The study reveals the potential of PA(N) in contributing to host protein shutdown during influenza A infection. Inhibition of viral RdRP's endonuclease activity is seen as a promising avenue for novel antiviral therapy. By developing a ligand-based pharmacophore model, structurally diverse compounds with better efficacy as PA(N) endonuclease inhibitors can be envisaged.
Article
Chemistry, Multidisciplinary
Marina Gardonyi, Christian Hasewinkel, Johanna Wallbaum, Jan Wollenhaupt, Manfred S. Weiss, Gerhard Klebe, Klaus Reuter, Andreas Heine
Summary: A high-resolution crystal structure of the Shigella pathogenicity factor IpgC was determined, revealing its potential as a target for anti-shigellosis compounds. Multiple small molecules that bind to IpgC were identified, providing a promising starting point for the design of functional IpgC inhibitors.
Article
Chemistry, Medicinal
Tatjana Barthel, Jan Wollenhaupt, Gustavo M. A. Lima, Markus C. Wahl, Manfred S. Weiss
Summary: The identification of starting points for compound development is crucial in early-stage drug discovery. Crystallographic fragment screening provides structural information of the binding mode, increasing the efficiency of this step. In this study, crystallographic screening of a compound library was conducted, resulting in the identification of 269 hits distributed over 10 distinct binding sites on the protein-protein complex surface. The study demonstrates that hit clusters can identify known interaction sites and suggest potential additional interaction sites, thereby accelerating downstream compound optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Felix Torres, Matthias Buetikofer, Gabriela R. R. Stadler, Alois Renn, Harindranath Kadavath, Raitis Bobrovs, Kristaps Jaudzems, Roland Riek
Summary: Although nuclear magnetic resonance (NMR) is commonly used in fragment-based drug design, its lack of sensitivity has limited its implementation in high-throughput screening. However, photochemically induced dynamic nuclear polarization (photo-CIDNP) is a promising method that can improve the sensitivity of NMR. This research demonstrates the detection of weak binders using low micromolar concentrations, exploiting the polarization enhancement provided by photo-CIDNP and achieving faster interaction detection compared to standard techniques. Furthermore, an automated flow-through platform and a photo-CIDNP fragment library are presented, providing a comprehensive approach for fragment-based screening.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Liang Xiong, Xin Mao, Yinping Guo, Yangli Zhou, Mingxin Chen, Pei Chen, Shengyong Yang, Linli Li
Summary: The study identified Cpd8 and Cpd10 as highly potent and selective BPTF inhibitors through structure-guided optimization. These compounds have the potential to inhibit BPTF activity based on experimental results.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Ross P. Thomas, Rachel E. Heap, Francesca Zappacosta, Emma K. Grant, Peter Pogany, Stephen Besley, David J. Fallon, Michael M. Hann, David House, Nicholas C. O. Tomkinson, Jacob T. Bush
Summary: The study introduces a screening platform that combines 'direct-to-biology' high-throughput chemistry with photoreactive fragments for rapid synthesis and screening of chemical tools. The platform allows for iterative design-make-test cycles to accelerate the development and optimization of chemical tools and medicinal chemistry starting points with minimal resource investment.
Article
Multidisciplinary Sciences
Marion Schuller, Galen J. Correy, Stefan Gahbauer, Daren Fearon, Taiasean Wu, Roberto Efrain Diaz, Iris D. Young, Luan Carvalho Martins, Dominique H. Smith, Ursula Schulze-Gahmen, Tristan W. Owens, Ishan Deshpande, Gregory E. Merz, Aye C. Thwin, Justin T. Biel, Jessica K. Peters, Michelle Moritz, Nadia Herrera, Huong T. Kratochvil, Anthony Aimon, James M. Bennett, Jose Brandao Neto, Aina E. Cohen, Alexandre Dias, Alice Douangamath, Louise Dunnett, Oleg Fedorov, Matteo P. Ferla, Martin R. Fuchs, Tyler J. Gorrie-Stone, James M. Holton, Michael G. Johnson, Tobias Krojer, George Meig, Ailsa J. Powell, Johannes Gregor Matthias Rack, Victor L. Rangel, Silvia Russi, Rachael E. Skyner, Clyde A. Smith, Alexei S. Soares, Jennifer L. Wierman, Kang Zhu, Peter O'Brien, Natalia Jura, Alan Ashworth, John J. Irwin, Michael C. Thompson, Jason E. Gestwicki, Frank von Delft, Brian K. Shoichet, James S. Fraser, Ivan Ahel
Summary: A large-scale crystallographic screening and computational docking effort identified new chemical matter targeting the active site of the SARS-CoV-2 macrodomain, providing a starting point for the development of potent macro-domain inhibitors.
Review
Pharmacology & Pharmacy
Hershna Patel, Andreas Kukol
Summary: This review provides a brief overview of molecular modelling in drug discovery, focusing on the integration of these methods with potential influenza A antiviral drug targets and discussing their advances and impact.
DRUG DISCOVERY TODAY
(2021)
Article
Biochemistry & Molecular Biology
Chengqian Wei, Junjie Huang, Yu Wang, Yifang Chen, Xin Luo, Shaobo Wang, Zengxue Wu, Jixiang Chen
Summary: A series of new oxadiazole sulfone derivatives containing an amide moiety were synthesized to screen high-efficiency antibacterial agents for rice bacterial diseases. Compound 10 showed excellent antibacterial activity against Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola, with EC50 values superior to commercial bactericides. Compound 10 demonstrated superior protective and curative activities against rice bacterial leaf blight and rice bacterial leaf streak compared to other tested compounds. Additionally, compound 10 exhibited potential mechanisms of action by affecting extracellular polysaccharides, cell membranes, and enzyme activity of dihydrolipoamide S-succinyltransferase to inhibit the growth of Xanthomonas oryzae pv. oryzae and Xanthomonas oryzae pv. oryzicola.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Dongyan Gu, Mengmeng Zhang, Lvtao Cai, Chang Wang, Yu -Bo Zhou, Jia Li, Rong Sheng
Summary: Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a hit for inhibiting PI3K alpha activity through virtual screening. Structural modifications based on similarity search and molecular docking yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited improved PI3K alpha inhibitory activity with good isoform selectivity and demonstrated promising pharmacokinetic properties. Further development of compound 49b as a potential PI3Ka inhibitor is warranted.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Muhammad Faheem, Napoleao Fonseca Valadares, Jose Brandao-Neto, Dom Bellini, Patrick Collins, Nicholas M. Pearce, Louise Bird, Juliana Roberta Torini, Raymond Owens, Humberto DMuniz Pereira, Frank Von Delft, Joao Alexandre Ribeiro Goncalves Barbosa
Summary: Schistosomiasis is an endemic disease in 78 countries, ranking second among parasitic diseases in terms of its socioeconomic impact and human health importance. The drug of choice for treatment, praziquantel, has limitations such as unclear mechanism, high cost, efficacy only against adult parasites, and reports of resistance. The lack of a de novo purine pathway in the parasites makes the purine salvage pathway an attractive target for the development of necessary and selective drugs.
BIOCHEMICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Xing-Xing Shi, Zhi-Zheng Wang, Fan Wang, Ge-Fei Hao, Guang-Fu Yang
Summary: Drug discovery is a crucial challenge for maintaining human health, and fragment-based drug discovery is a strategy for identifying novel candidate compounds. ACFIS 2.0 is an online tool in FBDD that accurately identifies potential drug leads. The improvements of ACFIS 2.0 include increased accuracy in hit compound identification, improved rationality of protein-fragment binding mode, increased structural diversity, and comprehensive functionality for predicting molecular properties.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Virology
Kevin Chiem, Dario Lopez-Garcia, Javier Ortego, Luis Martinez-Sobrido, Marta L. DeDiego, Aitor Nogales
Summary: PA-X is a nonstructural protein of influenza A virus that modulates host immune response and virus pathogenicity. This study identified important amino acid residues in the PA-X protein that are crucial for its activity and provides insights for the development of antiviral drugs.
JOURNAL OF VIROLOGY
(2022)
Review
Chemistry, Multidisciplinary
Moustafa T. Mabrouk, Wei-Chiao Huang, Luis Martinez-Sobrido, Jonathan F. Lovell
Summary: The COVID-19 pandemic caused by SARS-CoV-2 has led to millions of deaths globally and emphasized the importance of vaccines. Advanced technologies have enabled rapid development and deployment of COVID-19 vaccines, although access is limited in many developing countries. Different vaccine platforms and nanomaterials have been used to develop COVID-19 vaccines. Continued development of vaccine technologies is crucial for dealing with the ongoing and future pandemics.
ADVANCED MATERIALS
(2022)
Article
Virology
Wenjuan Dong, Heather Mead, Lei Tian, Jun-Gyu Park, Juan Garcia, Sierra Jaramillo, Tasha Barr, Daniel S. Kollath, Vanessa K. Coyne, Nathan E. Stone, Ashley Jones, Jianying Zhang, Aimin Li, Li-Shu Wang, Martha Milanes-Yearsley, Jordi B. Torrelles, Luis Martinez-Sobrido, Paul S. Keim, Bridget Marie Barker, Michael A. Caligiuri, Jianhua Yu
Summary: The K18-hACE2 mouse model provides a comprehensive analysis of SARS-CoV-2 infection and shows that different viral doses lead to varying degrees of organ damage. This model accurately reproduces both severe and non-severe COVID-19 in humans, making it valuable for drug development.
JOURNAL OF VIROLOGY
(2022)
Article
Virology
Ting Y. Wong, Alexander M. Horspool, Brynnan P. Russ, Chengjin Ye, Katherine S. Lee, Michael T. Winters, Justin R. Bevere, Olivia A. Miller, Nathaniel A. Rader, Melissa Cooper, Theodore Kieffer, Julien Sourimant, Alexander L. Greninger, Richard K. Plemper, James Denvir, Holly A. Cyphert, Mariette Barbier, Jordi B. Torrelles, Ivan Martinez, Luis Martinez-Sobrido, F. Heath Damron
Summary: SARS-CoV-2 variants of concern (VoC) have enhanced immune evasion, as demonstrated in this study using passive immunization with human convalescent plasma (HCP). The efficacy of HCP generated to ancestral SARS-CoV-2 was tested against the Alpha, Beta, and Delta VoC in a mouse model. The results show that HCP was unable to control the lethality of these VoC strains, highlighting the need for in vivo models to evaluate emerging strains' immune evasion.
JOURNAL OF VIROLOGY
(2022)
Review
Multidisciplinary Sciences
Julien Sourimant, Carolin M. Lieber, Megha Aggarwal, Robert M. Cox, Josef D. Wolf, Jeong-Joong Yoon, Mart Toots, Chengin Ye, Zachary Sticher, Alexander A. Kolykhalov, Luis Martinez-Sobrido, Gregory R. Bluemling, Michael G. Natchus, George R. Painter, Richard K. Plemper
Summary: This study describes a drug called 4'-fluorouridine (4'-FlU), which has broad-spectrum antiviral effects and potential for the treatment of respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and related RNA virus infections. In vitro and in vivo experiments showed that 4'-FlU inhibited RSV, SARS-CoV-2, and related RNA viruses with high efficacy, making it a promising candidate for broad-spectrum therapeutics against respiratory viruses.
Article
Microbiology
Kevin Chiem, Jun-Gyu Park, Desarey Morales Vasquez, Richard K. Plemper, Jordi B. Torrelles, James J. Kobie, Mark R. Walter, Chengjin Ye, Luis Martinez-Sobrido
Summary: Despite the availability of vaccines and antivirals, the SARS-CoV-2 virus continues to cause the COVID-19 pandemic, affecting healthcare institutions worldwide. Previous studies have generated replicable forms of the virus that express fluorescent or luciferase reporter proteins to track viral infection in vitro and/or in vivo. However, the limitations of these approaches have prevented their use in specific assays or studies. In this study, researchers engineered a new form of the virus that expresses both fluorescent (mCherry) and luciferase (Nluc) reporter genes, allowing for better understanding of the virus's behavior in vitro and in vivo. This new model was successfully used to study viral infection and transmission in rodent models using in vivo imaging systems.
MICROBIOLOGY SPECTRUM
(2022)
Article
Microbiology
Wei-Chiao Huang, Kevin Chiem, Luis Martinez-Sobrido, Jonathan F. Lovell
Summary: The study demonstrates that intranasal administration of liposome-displayed SARS-CoV-2 receptor-binding domain (RBD) can induce antigen-specific immune responses in the lungs. Both intranasal and intramuscular immunization with sub-microgram doses of RBD liposomes provide full protection against lethal SARS-CoV-2 infection.
Article
Microbiology
Chengjin Ye, Luis Martinez-Sobrido
Summary: Reporter-expressing recombinant virus is a powerful tool for studying viral infection and therapeutic approaches. To facilitate COVID-19 research, we established a BAC-based reverse genetics system to rapidly generate rSARS-CoV-2 and engineered recombinant viruses with reporter genes. We shared this system and provided detailed technical steps to aid other laboratories in their investigations.
MICROBIOLOGY SPECTRUM
(2022)
Article
Immunology
Maria M. Lorenzo, Alejandro Marin-Lopez, Kevin Chiem, Luis Jimenez-Cabello, Irfan Ullah, Sergio Utrilla-Trigo, Eva Calvo-Pinilla, Gema Lorenzo, Sandra Moreno, Chengjin Ye, Jun-Gyu Park, Alejandro Matia, Alejandro Brun, Juana M. Sanchez-Puig, Aitor Nogales, Walther Mothes, Pradeep D. Uchil, Priti Kumar, Javier Ortego, Erol Fikrig, Luis Martinez-Sobrido, Rafael Blasco
Summary: The COVID-19 pandemic highlights the need for fast responses and reliable technologies for vaccine development. This study reports on the construction and preclinical testing of a recombinant MVA vaccine, with the MVA-Spf vaccine candidate showing higher levels of antibodies, a stronger T cell response, and a higher degree of protection.
Article
Microbiology
Michael Piepenbrink, Fatai Oladunni, Aitor Nogales, Ahmed M. Khalil, Theresa Fitzgerald, Madhubanti Basu, Christopher Fucile, David J. Topham, Alexander F. Rosenberg, Luis Martinez-Sobrido, James J. Kobie
Summary: Influenza A virus (IAV) infections pose a significant threat to public health due to the variable nature of the virus. This study shows that immunization with a seasonal inactivated influenza vaccine (IIV) can increase the levels of antibodies against H3N2 IAV, a strain known for its genetic drift. These antibodies have broad and potent antiviral activity and can protect against various H3N2 IAV strains. They also persist in the bone marrow, indicating their potential for long-term immunity. These findings contribute to the development of a universal influenza vaccine.
MICROBIOLOGY SPECTRUM
(2023)
Article
Microbiology
Kevin Chiem, Aitor Nogales, Maria Lorenzo, Desarey Morales Vasquez, Yan Xiang, Yogesh K. Gupta, Rafael Blasco, Juan Carlos de la Torre, Luis Martinez-Sobrido
Summary: Despite the eradication of smallpox, some orthopoxviruses, such as monkeypox virus (MPXV), remain important human pathogens. Vaccines for smallpox are effective against MPXV, but limited in access. Current antiviral treatments for MPXV are limited to two FDA-approved drugs. Therefore, there is an urgent need to discover novel antivirals for the treatment of MPXV and other potentially zoonotic orthopoxvirus infections. Here, we found 13 compounds that inhibit both VACV and MPXV, derived from two different libraries of compounds known to inhibit various RNA viruses.
MICROBIOLOGY SPECTRUM
(2023)
Article
Immunology
Luis Martinez-Sobrido, James J. Kobie
Article
Virology
Ahmed M. Khalil, Michael S. Piepenbrink, Ian Markham, Madhubanti Basu, Luis Martinez-Sobrido, James J. Kobie
Summary: IBV contributes significantly to morbidity and mortality, particularly in children, necessitating improvements in vaccines and treatments. A specific hMAb, 1092D4, has been found to have minimal dependence on Fc-effector functions for in vivo antiviral activity.
Review
Immunology
Ahlam Alasiri, Raya Soltane, Akram Hegazy, Ahmed Magdy Khalil, Sara H. Mahmoud, Ahmed A. Khalil, Luis Martinez-Sobrido, Ahmed Mostafa
Summary: Despite being widespread in wild birds and domestic poultry, human infections with highly pathogenic avian influenza H5Nx viruses have been limited since 1996. Few countries use vaccination as a control strategy, while most rely on culling infected flocks. China and Egypt are the major sites where vaccination has been employed, particularly for clade 2.3.4.4b H5N1 viruses. However, improper implementation of control strategies in Egypt has resulted in continuous outbreaks and virus evolution. Comprehensive surveillance in endemic areas is crucial to understand the public health risk of newly emerging immune-evasive or drug-resistant H5Nx variants.
Article
Chemistry, Medicinal
Kirill Gorshkov, Desarey Morales Vasquez, Kevin Chiem, Chengjin Ye, Bruce Nguyen Tran, Juan Carlos de la Torre, Thomas Moran, Catherine Z. Chen, Luis Martinez-Sobrido, Wei Zheng
Summary: This study reports a time-resolved fluorescence resonance energy transfer-based assay for detecting the SARS-CoV-2 nucleocapsid protein. This assay can be used for rapid compound screening and drug efficacy evaluation, and is of great importance for accelerating COVID-19 drug development.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)