Article
Engineering, Biomedical
Javad Garousi, Emma von Witting, Jesper Borin, Anzhelika Vorobyeva, Mohamed Altai, Olga Vorontsova, Mark W. Konijnenberg, Maryam Oroujeni, Anna Orlova, Vladimir Tolmachev, Sophia Hober
Summary: Molecular recognition in targeted therapeutics is usually based on immunoglobulins. Engineered scaffold proteins have provided new opportunities for targeted therapies due to their inexpensive production, high stability, and convenient modification of biodistribution. The modification of the biodistribution through fusion with albumin-binding domain has proven effective in reducing renal uptake and increasing tumor uptake, improving the targeting properties of ADAPT derivatives for radionuclide therapy.
Review
Agriculture, Multidisciplinary
Victoria Jackson, Linda Jordan, Ryan N. Burgin, Oliver J. S. McGaw, Calum W. Muir, Victor Ceban
Summary: Macrocyclic natural products and their derivatives are valuable sources for biologically active crop protection products. However, finding suitable starting points for lead generation can be challenging due to their size and structural complexity. In this study, alternative bicyclic isosteres were identified as replacements for the antifungal nine-membered macrocycle UK-2A using molecular modeling and electrostatic analysis. Structure-based conformational approach was then used to derivatize a series of heterocyclic replacements, resulting in promising fungicidal activity and exploration of structure-activity relationships.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jian Yan, Shiyang Sun, Wenjuan Zhang, Pengyun Li, Zhibing Zheng
Summary: The study established a molecular library by scaffold hopping with thalidomide and used multiple screening methods to identify five potential CRBN ligands. Docking analysis and molecular dynamics simulations showed that these five molecules formed key interactions with active site amino acid residues and marketed IMiDs, suggesting their potential as further optimization of CRBN ligands and development of proteolysis targeting chimeras.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2021)
Article
Biochemical Research Methods
Chunqiu Xia, Shi-Hao Feng, Ying Xia, Xiaoyong Pan, Hong-Bin Shen
Summary: Protein-ligand binding affinity prediction is a challenging task in structural bioinformatics for drug discovery and design. Existing methods using scoring functions (SFs) for evaluation may have potential biases. A novel empirical graph neural network (EGNA) is proposed to accurately predict binding affinity by effectively representing proteins and ligands using graph convolutional layers and capturing interaction patterns. EGNA outperforms state-of-the-art machine learning-based SFs, demonstrating its superiority and generalization capability.
BRIEFINGS IN BIOINFORMATICS
(2023)
Article
Hematology
Joseph S. Gish, Lexi Jarvis, Kenneth C. Childers, Shaun C. Peters, Connor S. Garrels, Ian W. Smith, H. Trent Spencer, Christopher B. Doering, Pete Lollar, P. Clint Spiegel
Summary: The study reveals the structure of a therapeutically active fVIII construct complexed with an anti-C1 domain inhibitor, shedding light on the interaction between the antibody and fVIII, which may lead to the development of more effective and safe fVIII replacement therapies.
Article
Biochemistry & Molecular Biology
Alexander W. Weig, Samantha L. Barlock, Patrick M. O'Connor, Orry M. Marciano, Richard Smith, Robert K. Ernst, Roberta J. Melander, Christian Melander
Summary: Infections stemming from bacterial biofilms are difficult to eradicate, requiring the development of alternative treatment approaches. Pairing small molecule adjuvants with conventional antibiotics can effectively treat these infections. New aryl 2-AP analogs generated through a scaffold hopping strategy show potential in inhibiting biofilm formation and resistance in bacteria.
RSC MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Neda Fayyazi, Tahereh Mostashari-Rad, Jahan B. Ghasemi, Mehran Mirabzadeh Ardakani, Farzad Kobarfard
Summary: In this study, various computational methods were used to identify potential inhibitors for multiple targets associated with COVID-19, including 3CLpro and RdRp. Through virtual screening and other techniques, several promising compounds were discovered, demonstrating their potential as inhibitors for the two targets. Structure simulations and pharmacophore modeling revealed that specific residues play critical roles in dual activities, showcasing the importance of hydrogen bond features in the binding sites.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Stefan Engelhardt, Adriana Trutzenberg, Michaela Kopischke, Katja Probst, Christopher McCollum, Johanna Hofer, Ralph Hueckelhoven
Summary: Successful pathogens benefit from host cellular processes. The small monomeric G-protein RACB is required for susceptibility of Blumeria hordei to fungal penetration in barley. RACB can interact with the host protein RIC157, promoting fungal penetration into barley epidermal cells.
PLANT MOLECULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Adam Leach, Ami Miller, Emma Bentley, Giada Mattiuzzo, Jemima Thomas, Craig McAndrew, Rob Van Montfort, Terence Rabbitts
Summary: This study enhances the performance of anti-SARS-CoV-2 antibodies through multimerization, yielding tetrameric antibodies with efficient binding, enhanced neutralization, and potent interaction with virus variants. The method is a powerful tool for developing SARS-CoV-2 antibodies in pre-clinical and clinical investigations.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Justin Lawrie, Sean Waldrop, Anya Morozov, Wei Niu, Jiantao Guo
Summary: Protein tyrosine O-sulfation is crucial for various biological processes, but sulfated tyrosine residues are challenging to detect due to their instability and low abundance. This study engineered SH2 mutants as an antisulfotyrosine antibody mimic, demonstrating high affinity and specificity to sulfotyrosine through tailored selection schemes. Molecular docking simulations supported the characteristics of these SH2 mutants, enhancing the detection and enrichment of sulfoproteins.
ACS CHEMICAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Mieke Nys, Eleftherios Zarkadas, Marijke Brams, Aujan Mehregan, Kumiko Kambara, Jeroen Kool, Nicholas R. Casewell, Daniel Bertrand, John E. Baenziger, Hugues Nury, Chris Ulens
Summary: This study reveals the structure of the complex formed between muscle-type Torpedo receptor and a recombinant short-chain alpha-neurotoxin, providing insights into the interaction and specific inhibition mechanism of the toxin on the receptor. The findings explain the stronger binding of the toxin to muscle-type receptors compared to neuronal receptors.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Arien Schiepers, Marije F. L. van't Wout, Allison J. J. Greaney, Trinity Zang, Hiromi Muramatsu, Paulo J. C. Lin, Ying K. K. Tam, Luka Mesin, Tyler N. N. Starr, Paul D. D. Bieniasz, Norbert Pardi, Jesse D. D. Bloom, Gabriel D. D. Victora
Summary: The effectiveness of serum antibodies in providing protection is determined by the interactions between antigen-specific B cell clones with different affinities and specificities. These interactions lead to phenomena such as original antigenic sin (OAS), where the immune system relies on the initial cohort of B cells activated by an antigenic stimulus instead of inducing new responses. This suppression of new antibody responses may hinder vaccination against rapidly evolving viruses, highlighting the importance of understanding and addressing OAS for the design of effective vaccines.
Article
Multidisciplinary Sciences
Martina Sola, Azucena Rendon-Angel, Viviana Rojo Martinez, Jacopo Sgrignani, Claudia Magrin, Ester Piovesana, Andrea Cavalli, Paolo Paganetti, Stephanie Papin
Summary: Mutations in the Tau gene cause progressive dementia and the deposition of neurotoxic Tau forms in neurofibrillary tangles is a characteristic feature of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. Additionally, Tau interacts with MDM2 and affects P53 activity, and aberrant accumulation of MDM2 in neurofibrillary tangles suggests a potential role in neurodegeneration. These findings highlight a novel loss-of-function of Tau in both neurodegeneration and cancer.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Marwa H. El-Wakil, Mohamed Teleb
Summary: Novel 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazin-4-one derivatives were designed as Type I c-Met kinase inhibitors, with compound 5d identified as the most potent inhibitor against c-Met and showing selective antitumor activity against colon and lung adenocarcinoma cells over-expressing c-Met. These findings highlight 5d as a potential dual acting inhibitor that warrants further investigation for the development of new generation antitumor agents.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Lela Stefanovic, Blaine H. Gordon, Robert Silvers, Branko Stefanovic
Summary: Excessive synthesis of type I collagen is a hallmark of fibrotic diseases. LARP6 plays a key role in regulating collagen biosynthesis by binding to the 5'SL of collagen mRNAs. The La domain of LARP6, specifically the RNK motif, is essential for recognizing and binding to 5'SL RNA in a sequence-specific manner.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Giulia Torrieri, Monica P. A. Ferreira, Mohammad-Ali Shahbazi, Virpi Talman, S. Tuuli Karhu, Lotta Pohjolainen, Claudia Carvalho, Joao F. Pinto, Jouni Hirvonen, Heikki Ruskoaho, Vimalkumar Balasubramanian, Helder A. Santos
Summary: The developed nanosystem has the capability to stimulate cardiomyocyte proliferation and reduce fibrosis by approximately 80%, showing potential benefits for future in vivo applications.
ADVANCED FUNCTIONAL MATERIALS
(2022)
Article
Biochemical Research Methods
Angela Serra, Michele Fratello, Antonio Federico, Ravi Ojha, Riccardo Provenzani, Ervin Tasnadi, Luca Cattelani, Giusy del Giudice, Pia A. S. Kinaret, Laura A. Saarimaki, Alisa Pavel, Suvi Kuivanen, Vincenzo Cerullo, Olli Vapalahti, Peter Horvath, Antonio Di Lieto, Jari Yli-Kauhaluoma, Giuseppe Balistreri, Dario Greco
Summary: In the fight against the COVID-19 pandemic, there is a shift towards computational methods in drug discovery. Through virtual screening and chemical substructure extraction, two potential antiviral drugs have been identified. These methods provide some help in the search for new effective drugs.
BRIEFINGS IN BIOINFORMATICS
(2022)
Article
Neurosciences
Eline Huethorst, Peter Mortensen, Radostin D. Simitev, Hao Gao, Lotta Pohjolainen, Virpi Talman, Heikki Ruskoaho, Francis L. Burton, Nikolaj Gadegaard, Godfrey L. Smith
Summary: Human induced pluripotent stem cell-derived cardiomyocytes in monolayers exhibit multiphasic contractile profiles on rigid surfaces but normal twitch-like kinetics on flexible substrates. Isoprenaline has greater lusitropic and chronotropic effects on flexible substrates compared to glass, while there is no significant difference in stress-activated gene expression between stiff and flexible substrates. Computational models show complex contractile interactions on stiff substrates due to cell-to-cell functional heterogeneity.
JOURNAL OF PHYSIOLOGY-LONDON
(2022)
Review
Biochemistry & Molecular Biology
Aiva Plotniece, Arkadij Sobolev, Claudiu T. Supuran, Fabrizio Carta, Fredrik Bjoerkling, Henrik Franzyk, Jari Yli-Kauhaluoma, Koen Augustyns, Paul Cos, Linda De Vooght, Matthias Govaerts, Juliana Aizawa, Paeivi Tammela, Raivis Zalubovskis
Summary: Natural products and analogues are valuable sources for the discovery of antibacterial drugs. The identification of bacterial metalloenzymes and the synthesis of selective inhibitors are interesting for the development of antibacterial agents due to increasing drug resistance. Peptide nucleic acids represent a novel strategy for targeting pathogens through antisense inhibition and development of antisense peptide nucleic acids. The review also discusses alternative therapeutic options and optimized in vitro and in vivo models for studying biofilm-related infections along with an overview of drug delivery nanosystems.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Karine Mardon, Jayendra Z. Patel, Juha R. Savinainen, Damion H. R. Stimson, Caitlin R. M. Oyagawa, Natasha L. Grimsey, Mary-anne Migotto, Grace F. M. Njiru, Brett R. Hamilton, Gary Cowin, Jari Yli-Kauhaluoma, Wim Vanduffel, Idriss Blakey, Rajiv Bhalla, Christopher Cawthorne, Sofie Celen, Guy Bormans, Kristofer J. Thurecht, Muneer Ahamed
Summary: Multimodal imaging, through PET and MALDI imaging, is used to discover and validate a new probe targeting the ABHD6 enzyme. The PET ligand [18F]JZP-MA-11 is reported to have specific uptake in ABHD6-rich tissues and major brain regions, with brain uptake confirmed in a nonhuman primate study. In vivo pharmacological response upon ABHD6 inhibition is observed using MALDI imaging. These synergistic imaging efforts hold promise for improving our understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Food Science & Technology
Kirsi Savijoki, Paola San-Martin-Galindo, Katriina Pitkaenen, Minnamari Edelmann, Annika Sillanpaeae, Cim van der Velde, Ilkka Miettinen, Jayendra Z. Patel, Jari Yli-Kauhaluoma, Mataleena Parikka, Adyary Fallarero, Pekka Varmanen
Summary: By studying the effects of metabolic end-products of food-associated lactobacilli and propionibacteria on biofilm formation of Gram-negative pathogenic bacteria, it was found that these end-products can disrupt the quorum sensing system of the pathogenic bacteria, leading to the inhibition of biofilm formation.
Article
Biochemistry & Molecular Biology
Teppo O. Leino, Ainoleena Turku, Lauri Urvas, Karuna Adhikari, Jouni Oksanen, Yana Steynen, Jari Yli-Kauhaluoma, Henri Xhaard, Jyrki P. Kukkonen, Erik A. A. Wallen
Summary: The rare ring structure Azulene was investigated as a possible biphenyl mimetic for the orexin receptor agonist Nag 26. The most potent compound based on Azulene was identified as an OX1 orexin receptor agonist, but the spatial shape and electron distribution of the Azulene ring and biphenyl scaffold are not identical, suggesting different binding modes in the binding site for their derivatives.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anne-Sophie Depuydt, Piyush A. Patel, Zan Toplak, Chinmaya Bhat, Manuela Voracova, Irene Etelainen, Fiammetta Vitulano, Tanja Bruun, Antti Lempinen, Nives Hribernik, Eero Maki-Lohiluoma, Louise Hendrickx, Ernesto Lopes Pinheiro-Junior, Tihomir Tomasic, Lucija Peterlin Masic, Jari Yli-Kauhaluoma, Paula Kiuru, Jan Tytgat, Steve Peigneur
Summary: T-type calcium channels play important roles in cardiac function, and their dysfunction is associated with pathological conditions. In this study, a new class of T-type calcium channel inhibitors was discovered and their mechanism of action was investigated. These findings provide new insights into drug design and the interaction of drugs with T-type calcium channels.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Saara Lautala, Riccardo Provenzani, Ilari Tarvainen, Katia Sirna, S. Tuuli Karhu, Evgeni Grazhdankin, Antti K. Lehtinen, Hanan Sa'd, Artturi Koivuniemi, Henri Xhaard, Raimo K. Tuominen, Virpi Talman, Alex Bunker, Jari Yli-Kauhaluoma
Summary: Protein kinase C (PKC) modulators have therapeutic potential for various diseases. Targeting the C1 domain of PKC is a promising strategy, but the penetration of the lipid membrane complicates drug design. Molecular dynamics (MD) simulations with PKC, ligands, and membranes have been used to address these challenges. Here, we present the design, synthesis, and evaluation of new PKC agonists using an enhanced workflow with ligand-membrane MD simulations, which could be beneficial in designing ligands for weakly membrane-associated proteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Seyed Mehran Mirmohammadi, Kirsi Savijoki, Sasha Hoshian, Pekka Varmanen, Jari Yli-Kauhaluoma, Ville Jokinen, Sami Franssila
Summary: Copper has shown potential as a biomedical material with antibacterial properties. Combining copper with nanostructured surfaces that have superhydrophobic properties enhances the antibacterial effect. Three structured surfaces were tested, one with superhydrophobicity but without copper, one with copper but not superhydrophobic, and one with both superhydrophobicity and copper. The results showed that copper alone decreased cell viability in most tested species but supported more biomass compared to the reference sample. The superhydrophobic and copper-bearing sample exhibited the highest bactericidal effect against two strains of P. aeruginosa, and had antibiofilm and/or bactericidal effects against S. aureus and S. epidermidis.
ADVANCED MATERIALS INTERFACES
(2023)
Article
Chemistry, Medicinal
Tiina J. Ahonen, Choa P. Ng, Beatriz Farinha, Barbara Almeida, Bruno L. Victor, Christopher Reynolds, Eija Kalso, Jari Yli-Kauhaluoma, Jennifer Greaves, Vania M. Moreira
Summary: This study identified a class of highly selective inhibitors that can differentiate the inhibition of one enzyme from another. The structure-activity relationships presented here may inspire future drug discovery efforts in this field.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemical Research Methods
Alisa Pavel, Giusy del Giudice, Michele Fratello, Leo Ghemtio, Antonio Di Lieto, Jari Yli-Kauhaluoma, Henri Xhaard, Antonio Federico, Angela Serra, Dario Greco
Summary: In this study, a network mapping approach (KNeMAP) was proposed for comparing transcriptomic profiles. By grouping genes into similarity groups based on multiple levels of prior information, KNeMAP provided a higher-level view and showed higher accuracy in identifying compounds with similar molecular responses compared to traditional methods.
Article
Pharmacology & Pharmacy
Ilari Tarvainen, Rebecca C. Nunn, Raimo K. Tuominen, Maria H. Jantti, Virpi Talman
Summary: Colorectal cancer is a common cancer and its burden is expected to increase in the next 10 years. The protein kinase C (PKC)-modulating isophthalic acid derivative HMI-1a3 has been found to inhibit cell proliferation and induce apoptosis in colorectal cancer cell lines independent of PKC. It was discovered that HMI-1a3 activates the cAMP/PKA pathway, providing new insights for the development of PKC and PKA modulators for cancer therapy.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2022)