Article
Chemistry, Multidisciplinary
Eleanor L. Atkinson, Jessica Iegre, Claudio D'Amore, Paul Brear, Mauro Salvi, Marko Hyvonen, David R. Spring
Summary: In this study, an iterative cycle of enzymatic assays, X-ray crystallography, molecular modelling and cellular assays was used to develop a functionalisable chemical probe for the investigation of CK2α/β PPI. The lead peptide, P8C9, showed successful binding to CK2α at the PPI site, and it was found to be easily synthesizable and functionalisable. The peptide also exhibited high stability in serum and had potential for further optimization.
CHEMICAL COMMUNICATIONS
(2022)
Editorial Material
Pharmacology & Pharmacy
Marco P. Licciardello, Paul Workman
Summary: Casein kinase 2, a potential therapeutic target in cancer due to its high expression, did not exhibit broad antiproliferative activity in cancer cells when targeted by the new inhibitor SGC-CK2-1, developed by Wells and colleagues.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Manzar Alam, Md. Meraj Ansari, Saba Noor, Taj Mohammad, Gulam Mustafa Hasan, Syed Naqui Kazim, Md. Imtaiyaz Hassan
Summary: TBK1 plays a fundamental role in regulating cellular responses and controlling signaling cascades. Dysregulation of the TBK1 pathway is associated with various pathophysiological conditions. Inhibitors targeting TBK1 have potential therapeutic applications for diseases, including cancer.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Chemistry, Medicinal
Gulbag Kahlon, Rogelio Lira, Nikolay Masvlov, Emmett Pompa, Nimrat Brar, Scott Eagon, Marc O. Anderson, Armann Andaya, Jeff P. Chance, Hannah Fejzic, Aaron Keniston, Brian Vidal, Nicholas Trieu, Paulina Rodriguez, Jeremy P. Mallari
Summary: This study focused on investigating the function of the protease FLN in the protozoan parasite Plasmodium falciparum, which causes severe human malaria. The development of inhibitors targeting FLN showed significant improvements in potency against purified FLN and cultured P. falciparum, with computational studies predicting a binding model consistent with biochemical data.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Review
Plant Sciences
Renee Dale, Scott Oswald, Amogh Jalihal, Mary-Francis LaPorte, Daniel M. Fletcher, Allen Hubbard, Shin-Han Shiu, Andrew David Lyle Nelson, Alexander Bucksch
Summary: The study discusses the underutilization of computational modeling approaches in plant biology, particularly mechanistic mathematical modeling. It presents arguments for the adoption of modeling by plant biologists and provides suggestions for easy-to-use tools for non-specialists. The article emphasizes the importance of a thorough appreciation of different kinds of modeling for interdisciplinary, transformative research in plant biology.
FRONTIERS IN PLANT SCIENCE
(2021)
Review
Chemistry, Multidisciplinary
Yuhong Huang, Xiuling Ji, Zhanling Ma, Mateusz Lezyk, Yaju Xue, Hai Zhao
Summary: Cadaverine shows great potential as an important monomer for high value-added products with promising market prospects. The most effective strategies for its synthesis involve green chemical and bioconversion technologies. This review focuses on the progress, strategies, and challenging issues of cadaverine synthesis, biosynthesis, and purification, highlighting both environmental and economic impacts.
Review
Chemistry, Multidisciplinary
You-Yu Wang, Wenyi Li, Bang-Ce Ye, Xiao-Bao Bi
Summary: Protein-protein interactions (PPIs) are essential for cellular signal transduction. Studying PPIs without disrupting the functions of intact cells is crucial for basic biology research and drug development. Developing new methods with high efficiency and operability, such as advanced fluorescent microscopy and mass spectroscopy techniques, enables the visualization, monitoring, profiling, and identification of PPIs in a high-throughput manner, greatly aiding the understanding of molecular mechanisms underlying various pathophysiological processes.
CHEMISTRY-AN ASIAN JOURNAL
(2023)
Review
Biochemistry & Molecular Biology
Binu Jacob, Alicia Vogelaar, Enrique Cadenas, Julio A. Camarero
Summary: This review provides an overview of the properties of cyclotides and their potential for developing novel peptide-based therapeutics. Cyclotides, with their cell-permeability properties, have shown great promise for targeting biomolecular interactions. Molecular techniques employing the cyclotide scaffold have been highly effective for selecting bioactive cyclotides.
Review
Oncology
Sonia Missiroli, Mariasole Perrone, Caterina Boncompagni, Chiara Borghi, Alberto Campagnaro, Francesco Marchetti, Gabriele Anania, Pantaleo Greco, Francesco Fiorica, Paolo Pinton, Carlotta Giorgi
Summary: The NLRP3 inflammasome is a key player in cancer development, with inhibitors, antagonists, and monoclonal antibodies being considered as potential therapeutic approaches. Understanding NLRP3 inflammasome-dependent mechanisms in cancer may lead to the development of new drugs targeting tumor-associated inflammatory responses.
Review
Pharmacology & Pharmacy
Marina Buyanova, Dehua Pei
Summary: Intracellular protein-protein interactions are challenging targets for traditional drug modalities. Macrocyclic peptides have proven to be effective inhibitors, but they are generally impermeable to the cell membrane. Recent advances in MP science and technology have allowed for the development of cell-permeable MPs that can modulate intracellular PPI targets.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Review
Chemistry, Multidisciplinary
Adria Gil, Jorge J. Carbo
Summary: Computational modelling has played an important role in understanding the interaction and activity mechanisms of POMs with biological systems. Recent studies have focused on the binding analysis of POMs with proteins and other systems, and have revealed the nature of their interactions, as well as the impact of POM properties on protein affinity. Furthermore, computational studies have begun to elucidate the factors governing the hydrolysis activity and selectivity of peptide and phosphoester bonds by POMs.
FRONTIERS IN CHEMISTRY
(2022)
Article
Computer Science, Artificial Intelligence
Zaineb Chelly Dagdia, Pavel Avdeyev, Md. Shamsuzzoha Bayzid
Summary: Biological computation and computational biology involve the design and application of computational techniques inspired by natural biota, as well as the study of biological systems using computational techniques. This study highlights the mutual benefits between biology and computer science, and emphasizes how nature has influenced the development of computer science.
ARTIFICIAL INTELLIGENCE REVIEW
(2021)
Review
Oncology
Miyad Movassaghi, Rainjade Chung, Christopher B. Anderson, Mark Stein, Yvonne Saenger, Izak Faiena
Summary: Immunotherapy in prostate cancer faces challenges due to multiple interrelated mechanisms affecting treatment efficacy. Various strategies are being tested to overcome immune resistance, including combining different classes of treatment modalities. Studies have shown that combining vaccines or checkpoint inhibitors with other therapies may enhance immune responses and induce long-lasting clinical responses.
Review
Oncology
Shady I. Tantawy, Natalia Timofeeva, Aloke Sarkar, Varsha Gandhi
Summary: Evading apoptosis through overexpression of prosurvival BCL-2 family proteins, such as Mcl-1, is a mechanism that contributes to tumor development and chemoresistance. Targeting MCL-1 protein has shown success in inducing apoptosis and overcoming resistance to chemotherapy and targeted therapy. Various strategies to inhibit MCL-1's antiapoptotic activity have been explored, including targeting its interactions with other proteins.
FRONTIERS IN ONCOLOGY
(2023)
Review
Biotechnology & Applied Microbiology
Alessandra Biz, Radhakrishnan Mahadevan
Summary: This review discusses the challenge of high-level expression of bacterial iron-sulfur enzymes in yeast, pointing out the issue of intermediate accumulation. Possible explanations are proposed, genetic interventions are discussed, and future directions for improving yeast hosts for high iron-sulfur enzyme expression are suggested.
TRENDS IN BIOTECHNOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Stephen J. Walsh, Soleilmane Omarjee, Friederike M. Dannheim, Dominique-Laurent Couturier, Dorentina Bexheti, Lee Mendil, Gemma Cronshaw, Toby Fewster, Charlotte Gregg, Cara Brodie, Jodi L. Miller, Richard Houghton, Jason S. Carroll, David R. Spring
Summary: The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterization of the synthesized ADCs was first conducted, followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumors.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Organic
Martin Bargum, Mikkel Krell-Jorgensen, Martin Nielsen, Katrine Qvortrup, Luca Laraia
Summary: This article reports a microfluidic system for photochemical cycloadditions fabricated using silicon micro processing technologies. The optimized system enables the completion of a range of photochemical reactions in just a few minutes using high power UV-LEDs and triplet photosensitizers. The feasibility of performing photochemistry in microflow in an academic research environment is demonstrated, and a reaction leading to a novel scaffold and its mechanistic proposal are reported.
Article
Chemistry, Physical
David J. Huggins
Summary: This paper presents an approach to alchemical binding free energies using OpenMM and evaluates the prediction accuracy using benchmark test sets. The findings highlight the effectiveness of some AMBER forcefields, particularly AMBER ff15ipq.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Cecilia Rossetti, Luca Laraia
Summary: This study systematically investigated the roles of oxysterols in regulating human physiology. It was found that the site of oxidation has a profound impact on target selectivity, with each oxysterol possessing a unique set of target proteins. Additionally, the study revealed that the targets are clustered in pathways related to vesicular transport and phosphoinositide metabolism.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Radu Costin Bizga Nicolescu, Zoe R. Maylin, Francisco Javier Perez-Areales, Jessica Iegre, Hardev S. Pandha, Mohammad Asim, David R. Spring
Summary: This study reports the synthesis and biological characterization of a novel class of compounds covalently linking enzalutamide and EPI-001, which show significant improvement in cell killing potency towards prostate cancer cells compared to current therapies. The most promising compounds exhibit toxicity exclusively through androgen receptor mediated pathways, setting the basis for hybrid AR inhibitors combining EPI-001 and enzalutamide into a single molecule.
Article
Biochemistry & Molecular Biology
Thomas Whitmarsh-Everiss, Zhou Wang, Cecilie Hauberg Hansen, Laura Depta, Elisa Sassetti, Oliver Rafn Dan, Axel Pahl, Sonja Sievers, Luca Laraia
Summary: Combining natural product fragments to design new scaffolds with unprecedented bioactivity is an effective strategy for discovering useful compounds for tools and potential therapeutics. However, the choice of fragments to couple and the biological screens to use still remain unanswered questions. In this study, by combining a primary fragment containing the A/B ring system of estradiol with nine different secondary fragments, compounds that modulated four different phenotypes were identified. The use of unbiased morphological profiling with a cell-painting assay also revealed additional phenotypes that were not previously known. The discovery of a variety of biologically active compounds demonstrates the value of recombining natural product fragments with phenotypic screening for rapid compound identification.
Article
Chemistry, Multidisciplinary
Mikkel Krell-Jorgensen, Habiburrahman Zulfikri, Magnus Grage Bonnevie, Frederik Simonsen Bro, Asmus Ougaard Dohn, Luca Laraia
Summary: We report bistable indole-containing hemithioindigos (HTIs) with one-way quantitative photoswitching properties. A mechanism involving isomer-specific excited state intramolecular proton transfer (ESIPT) is proposed based on calculations. We also developed a thermally bistable oligomer-inspired bipyrrole-containing HTI that exhibits large band separation and bidirectional near-quantitative photoisomerization in the near-infrared, bio-optical window.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Nicola Ashman, Jonathan D. Bargh, Stephen J. Walsh, Ryan D. Greenwood, Arnaud Tiberghien, Jason S. Carroll, David R. Spring
Summary: Antibody-drug conjugates with peroxide-cleavable arylboronic acid linkers are developed to target cancer cells with high levels of reactive oxygen species (ROS). These linkers can rapidly release drugs in the presence of hydrogen peroxide while remaining stable in plasma. The peroxide-cleavable ADCs targeting HER2 and PD-L1 exhibit potent cytotoxicity in vitro.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Wei Chen, Di Cui, Steven V. Jerome, Mayako Michino, Eelke B. Lenselink, David J. Huggins, Alexandre Beautrait, Jeremie Vendome, Robert Abel, Richard A. Friesner, Lingle Wang
Summary: In the hit identification stage of drug discovery, absolute protein-ligand binding free-energy perturbation (ABFEP) is a theoretically rigorous and accurate method that can greatly improve hit rates in virtual screening. In this work, an implementation of ABFEP method in FEP+ was described and validated using different compounds and protein receptors. The calculated binding free energies showed good correlation with experimental results and demonstrated the usefulness of ABFEP in improving hit rates in virtual screening.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Ruwei Yao, Anders A. A. Jensen, Hogan P. P. Bryce-Rogers, Katrine Schultz-Knudsen, Libin Zhou, Nicklas P. P. Hovendal, Henrik Pedersen, Mariusz Kubus, Trond Ulven, Luca Laraia
Summary: The recombination of natural product fragments is an important strategy for discovering bioactive compounds. We synthesized a compound library enriched in spirocyclic ring fusions using alkaloid-inspired scaffolds. The library exhibited excellent drug-like properties and targeted screening led to the identification of hits with significant agonist or antagonist activity against specific serotonin and dopamine receptors. Optimization of one of these hits resulted in a promising lead compound with high selectivity as a dual 5-HT2B/C antagonist.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Paul Brear, Claudia De Fusco, Eleanor L. Atkinson, Jessica Iegre, Nicola J. Francis-Newton, Ashok R. Venkitaraman, Marko Hyvonen, David R. Spring
Summary: This study describes the development of a series of CK2 alpha allosteric inhibitors through iterative cycles of X-ray crystallography and enzymatic assays, in addition to both fragment growing and fragment merging design strategies. The lead fragment developed, fragment 8, exhibits high ligand efficiency and successful engagement with CK2 alpha in cells.
RSC MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Multidisciplinary
Nicola Ashman, Jonathan D. Bargh, David R. Spring
Summary: Traditional antibody-drug conjugates (ADCs) require internalisation into cancer cells, but this approach has limitations. Recent research has shown that extracellular release of drugs upon binding to poorly-internalising antigens or other tumoral components can overcome these limitations. This new approach has the potential to expand the range of cancer targets and improve treatment efficacy.
CHEMICAL SOCIETY REVIEWS
(2022)
Article
Chemistry, Multidisciplinary
Abigail R. Hanby, Stephen J. Walsh, Andrew J. Counsell, Nicola Ashman, Kim T. Mortensen, Jason S. Carroll, David R. Spring
Summary: In this study, a methodology for the dual-functionalisation of IgG antibodies is developed using disulfide rebridging divinylpyrimidine technology combined with bicyclononyne and methylcyclopropene handles for sequential SPAAC and IEDDA reactions. This strategy is advantageous as it does not require metal catalysis and avoids the need for purification between functionalisation steps.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Friederike M. Dannheim, Stephen J. Walsh, Carolina T. Orozco, Anders Hojgaard Hansen, Jonathan D. Bargh, Sophie E. Jackson, Nicholas J. Bond, Jeremy S. Parker, Jason S. Carroll, David R. Spring
Summary: This study reports a novel method for generating antibody conjugates with modular cargo loading using a new class of disulfide rebridging linkers. The approach allows all four interchain disulfides in an IgG1 antibody to be bridged with a single linker molecule by reacting with eight cysteine residues. Modulation of cargo loading can be achieved in a quick and selective manner by modifying the antibody with the linker in a 1 : 1 ratio and derivatizing the linker with varying numbers of payload attachment handles.
Article
Chemistry, Multidisciplinary
Eleanor L. Atkinson, Jessica Iegre, Claudio D'Amore, Paul Brear, Mauro Salvi, Marko Hyvonen, David R. Spring
Summary: In this study, an iterative cycle of enzymatic assays, X-ray crystallography, molecular modelling and cellular assays was used to develop a functionalisable chemical probe for the investigation of CK2α/β PPI. The lead peptide, P8C9, showed successful binding to CK2α at the PPI site, and it was found to be easily synthesizable and functionalisable. The peptide also exhibited high stability in serum and had potential for further optimization.
CHEMICAL COMMUNICATIONS
(2022)