Review
Pharmacology & Pharmacy
Johanna Giovannini, Willy Smeralda, Marie Jouanne, Jana Sopkova-de Oliveira Santos, Marco Catto, Anne Sophie Voisin-Chiret
Summary: Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein in the brain, with Alzheimer's disease being the most common form. The pathophysiological mechanisms of AD are still not fully understood, and there is currently no curative treatment available. Therefore, targeting tau protein aggregation has become an important focus for therapeutic approaches.
DRUG DISCOVERY TODAY
(2022)
Article
Chemistry, Multidisciplinary
Linlin Xu, Yuxun Ding, Feihe Ma, Yue Chen, Guidong Chen, Lin Zhu, Jiafu Long, Rujiang Ma, Yang Liu, Jianfeng Liu, Fan Huang, Linqi Shi
Summary: Researchers have developed a customized nanochaperone protein for targeting intracellular pathological tau in Alzheimer's disease. This protein effectively inhibits tau aggregation and improves cognitive deficits. The nanochaperone exhibits selectivity and does not interfere with normal tau function. This study provides valuable insights for the treatment of Alzheimer's disease and other neurodegenerative disorders.
Article
Nanoscience & Nanotechnology
Lin Zhu, Linlin Xu, Xiaohui Wu, Fei Deng, Rujiang Ma, Yang Liu, Fan Huang, Linqi Shi
Summary: With traditional drugs failing in AD treatment, tau protein has emerged as a new therapeutic target. A multifunctional nano-inhibitor based on nanotechnology has been developed to inhibit tau aggregation, degrade tau aggregates, and reduce their toxicity to neural cells.
ACS APPLIED MATERIALS & INTERFACES
(2021)
Article
Cardiac & Cardiovascular Systems
Marco Luciani, Mauro Montalbano, Luca Troncone, Camilla Bacchin, Keita Uchida, Gianlorenzo Daniele, Bethany Jacobs Wolf, Helen M. Butler, Justin Kiel, Stefano Berto, Cortney Gensemer, Kelsey Moore, Jordan Morningstar, Thamonwan Diteepeng, Onder Albayram, Jose F. Abisambra, Russell A. Norris, Thomas G. Di Salvo, Benjamin Prosser, Rakez Kayed, Federica del Monte
Summary: This study found that Tau protein is expressed and aggregates in the heart tissue of patients with heart failure and Alzheimer's disease. Furthermore, monoclonal antibody therapy can improve heart function and clear toxic aggregates, suggesting that Tau may be a potential target for heart failure treatment.
EUROPEAN HEART JOURNAL
(2023)
Article
Chemistry, Medicinal
Yiwei Zhang, Jiabei Guo, Jiongjia Cheng, Zhenghua Zhang, Fenghua Kang, Xiaoxing Wu, Qian Chu
Summary: Therapeutic peptides have revolutionized treatment for many human diseases. In recent decades, stapled helical peptides have made rapid progress in drug discovery. Compared to unstabilized linear peptides, stapled helical peptides have shown superior binding affinity, selectivity, membrane permeability, and metabolic stability, offering exciting potential for targeting challenging protein-protein interfaces. This Perspective summarizes the recent use of high-throughput screening technologies for identifying potent stapled helical peptides with optimized binding properties, aiming to accelerate the development of stapled helical peptides as the next generation of therapeutic peptides for various human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Christin Pohl, Sujata Mahapatra, Alina Kulakova, Werner Streicher, Gunther H. J. Peters, Allan Norgaard, Pernille Harris
Summary: This study applies small angle X-ray scattering (SAXS), which is not typically used in industrial protein screening, in a high throughput screening workflow to address problems of contradicting results and reproducibility among different methods. The results demonstrate that SAXS can provide valuable information on interparticle interactions, even without time-consuming modeling, and can be used as a tool for in-depth knowledge highly useful for protein formulation development.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Ying-Ying Gao, Tao Zhong, Li-Qiang Wang, Na Zhang, Yan Zeng, Ji-Ying Hu, Hai-Bin Dang, Jie Chen, Yi Liang
Summary: Zinc promotes liquid-liquid phase separation and aggregation of full-length Tau, resulting in the formation of stress granules and interaction with G3BP1, leading to increased Tau filaments and neuronal toxicity. Additionally, zinc aggravates mitochondrial damage and reactive oxygen species production induced by Tau aggregation, further deteriorating the pathogenesis of Alzheimer's disease.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Computer Science, Artificial Intelligence
Daniel R. Wong, Jay Conrad, Noah R. Johnson, Jacob Ayers, Annelies Laeremans, Joanne C. Lee, Jisoo Lee, Stanley B. Prusiner, Sourav Bandyopadhyay, Atul J. Butte, Nick A. Paras, Michael J. Keiser
Summary: This study develops a deep learning method for generating images in drug discovery, with broad applicability across diverse fluorescence microscopy datasets.
NATURE MACHINE INTELLIGENCE
(2022)
Article
Multidisciplinary Sciences
Priyanka Parijat, Saraswathi Ponnam, Seetharamaiah Attili, Kenneth S. Campbell, Mohammed El-Mezgueldi, Mark Pfuhl, Thomas Kampourakis
Summary: The unmet demand for new heart failure therapeutics is well recognized and targeting the contractile myofilaments has shown potential for the development of new drugs. However, limited clinical use and incomplete understanding of myofilament function have hindered progress in this area. In this study, new high throughput screening platforms were designed and validated to explore the effects of small molecule effectors on the interactions between cardiac troponin C and troponin I subunits. The results suggest that sarcomeric protein-directed screening platforms are suitable for developing compounds that modulate cardiac myofilament function.
SCIENTIFIC REPORTS
(2023)
Article
Medicine, Research & Experimental
Rit Pratik Mishra, Surbhi Gupta, Anurag Singh Rathore, Gaurav Goel
Summary: A multi-level virtual screening protocol is developed to identify lead molecules that can inhibit insulin aggregation. The protocol involves multiple steps, including screening the inactives database, docking and molecular dynamics simulations, and experimental validation. Riboflavin is identified as the most effective lead molecule for inhibiting insulin aggregation.
MOLECULAR PHARMACEUTICS
(2022)
Review
Biochemistry & Molecular Biology
Filippa Lo Cascio, Paola Marzullo, Rakez Kayed, Antonio Palumbo Piccionello
Summary: This review highlights recent research on modifying the structure of curcumin to search for new effective therapeutic agents against neurodegenerative diseases, with a particular focus on Alzheimer's disease.
Article
Biochemistry & Molecular Biology
Yanli Sun, Haibo Lu, Xueyu Fang, Senhao Xiao, Feng Yang, Yantao Chen, Hongbo Wang, Xiaopeng Li, Jing Lu, Hua Lin, Cheng Luo, Kehao Zhao, Shijie Chen
Summary: Tumor suppressor p53-binding protein 1 (53BP1) plays a crucial role in DNA Damage Repair pathways and its dysregulation is associated with various diseases including cancer. Recent studies have identified a novel and effective 53BP1-TTD inhibitor DP308, disrupting the binding between 53BP1 and H4K20me2 peptide, showing promise as a potential tool for further optimization of biological functions and gene editing therapies.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Zdenek Fisar
Summary: Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with A beta neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of A beta oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly A beta oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.
Article
Immunology
Xiaojing Wen, Li Zhang, Shan Zhao, Qiang Liu, Wenyi Guan, Jiajing Wu, Qiwei Zhang, Hongling Wen, Weijin Huang
Summary: The study found that cardamomin has good anti-human adenovirus 5 (HAdV5) activity both in vitro and in vivo, and can protect tissues from virus-induced damage. This research established a method for high-throughput screening of anti-HAdV5 drugs and demonstrated cardamomin as a potential new treatment for patients infected with adenoviruses.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Tomohiro Tsuchida, Kouki Susa, Tomohiro Kibiki, Takahiro Tsuchiya, Katsushiro Miyamoto, Yasuko In, Katsuhiko Minoura, Taizo Taniguchi, Toshimasa Ishida, Koji Tomoo
Summary: A study identified a new approach to inhibit tau aggregation by targeting the VQIINK region, providing a novel strategy for the treatment of Alzheimer's disease.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Chemistry, Physical
Thomas C. T. Michaels, Alexander J. Dear, Samuel I. A. Cohen, Michele Vendruscolo, Tuomas P. J. Knowles
Summary: Protein self-assembly into amyloid fibrils is crucial for neurodegenerative diseases, with small oligomers formed during this process being neurotoxic species associated with amyloid aggregation. Targeting the formation of oligomers may be a possible therapeutic avenue. Through a kinetic model, researchers have identified key kinetic parameters that effectively control the generation of oligomers, opening up new possibilities for therapeutic strategies against amyloid-related diseases.
JOURNAL OF CHEMICAL PHYSICS
(2022)
Review
Biochemistry & Molecular Biology
Ryan Limbocker, Silvia Errico, Denise Barbut, Tuomas P. J. Knowles, Michele Vendruscolo, Fabrizio Chiti, Michael Zasloff
Summary: Alzheimer's and Parkinson's diseases, affecting over 50 million people worldwide, are still largely intractable pharmacologically. Research suggests that natural products squalamine and trodusquemine offer promising opportunities for chronic treatments by preventing the formation of neurotoxic oligomers and their interaction with cell membranes.
NATURAL PRODUCT REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Andras Hatos, Silvio C. E. Tosatto, Michele Vendruscolo, Monika Fuxreiter
Summary: The FuzDrop method predicts the probability of phase separation and aggregation of proteins, and identifies the relevant regions. It is significant for studying the functional relationships of proteins.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Thomas Lohr, Pietro Sormanni, Michele Vendruscolo
Summary: The emerging field of in silico antibody discovery offers a promising alternative to traditional in vivo and in vitro approaches, but faces challenges in matching the properties of designed antibodies to those produced by the immune system. Structural features and conformational entropy play crucial roles in determining the stability and binding affinity of computer-designed antibodies. Enhanced-sampling molecular dynamics simulations reveal differences in conformational heterogeneity and dynamics of designed antibodies compared to a nanobody derived from llama immunization, highlighting the complexities in rational antibody design.
Article
Biochemical Research Methods
Marc Oeller, Ryan Kang, Rosie Bell, Hannes Ausserwoger, Pietro Sormanni, Michele Vendruscolo
Summary: This article describes a computational method that incorporates the effect of pH on protein solubility predictions. The accuracy of these predictions is comparable to experimental methods, as demonstrated on various antibodies and proteins. This method, named CamSol 3.0, is now publicly available at https://www-cohsoftware.ch.cam.ac.uk/index.php/camsolph.
BRIEFINGS IN BIOINFORMATICS
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Sean Chia, Zenon Toprakcioglu, Tuuli Hakala, Roman Schmid, Yaduo Feng, Tadas Kartanas, Ayaka Kamada, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: In this study, a lab-on-a-chip spray approach was developed to combine rapid sample preparation, mixing, and deposition with nanoanalytical methods in chemistry and biology. This method provides enhanced spectroscopic sensitivity and single-molecule spatial resolution, allowing for multidimensional studies of heterogeneous biomolecular systems.
Review
Chemistry, Multidisciplinary
Ryan Limbocker, Nunilo Cremades, Roberta Cascella, Peter M. Tessier, Michele Vendruscolo, Fabrizio Chiti
Summary: The misfolding and aggregation of peptides and proteins into amyloid aggregates is a common feature of various protein misfolding diseases, including Alzheimer's disease and Parkinson's disease. Misfolded protein oligomers, which can form intermediates in the fibril formation process or be released by mature fibrils, are increasingly recognized as central to the development of these diseases. Despite challenges in studying these oligomers, researchers have developed methods to produce stable and reproducible populations for experimentation. These tools have provided insights into the structural determinants of oligomer toxicity and potential therapeutic strategies.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Review
Pharmacology & Pharmacy
Michele Vendruscolo
Summary: Protein misfolding diseases, such as Alzheimer's and Parkinson's diseases, have a major impact on our healthcare systems and societies. This paper discusses drug discovery strategies to target protein misfolding and aggregation, including thermodynamic and kinetic approaches. There is a need for disease-modifying treatments to address the over 50 human disorders associated with protein misfolding and aggregation.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Review
Clinical Neurology
Mark R. Wilson, Sandeep Satapathy, Michele Vendruscolo
Summary: The proteostasis system regulates cellular processes of protein synthesis, folding, concentration, trafficking, and degradation. The mechanisms of extracellular proteostasis, particularly in the context of neurodegenerative diseases, are not well understood, but growing evidence suggests that impairment of this system may contribute to neuronal death.
NATURE REVIEWS NEUROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Andras Hatos, Joao M. C. Teixeira, Susana Barrera-Vilarmau, Attila Horvath, Silvio C. E. Tosatto, Michele Vendruscolo, Monika Fuxreiter
Summary: Proteins form complex interactions in the cellular environment. The FuzPred server predicts their binding modes based on sequence without specifying the binding partners. The server also estimates the multiplicity of binding modes and visualizes different interaction behaviors on protein structures.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Alyssa Miller, Jiapeng Wei, Sarah Meehan, Christopher M. Dobson, Mark E. Welland, David Klenerman, Michele Vendruscolo, Francesco Simone Ruggeri, Tuomas P. J. Knowles
Summary: Neurodegenerative diseases such as Alzheimer's disease are caused by protein misfolding and aggregation into amyloid fibrils. This study uses atomic force microscopy and statistical theory to characterize amyloid ring structures derived from the brains of AD patients and explains the diversity in the structures formed from protein aggregation. The results show that ex vivo protofibril chains possess greater flexibility than mature amyloid fibrils, allowing them to form end-to-end connections and shedding light on their role in disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Z. Faidon Brotzakis, Thomas Lohr, Steven Truong, Samuel Hoff, Massimiliano Bonomi, Michele Vendruscolo
Summary: In recent years, cryo-electron microscopy has made significant advancements in determining biomolecular structures at the atomic level. However, studying large systems with continuous dynamics using this method has been a challenge. To address this, the metadynamic electron microscopy metainference (MEMMI) method was developed, which combines cryo-EM density maps with prior information to determine the structure and dynamics of large heterogeneous systems. This method was applied to study the amyloid fibril dynamics of the islet amyloid polypeptide (IAPP), revealing interesting characteristics of the fibril's structural variability and liquid-like dynamics in the core region.
Article
Multidisciplinary Sciences
Christine M. Lim, Alicia Gonzalez Diaz, Monika Fuxreiter, Frank W. Pun, Alex Zhavoronkov, Michele Vendruscolo
Summary: This study presents an approach that combines the PandaOmics platform with the FuzDrop method to identify disease-associated proteins prone to protein phase separation (PPS). The validated targets for Alzheimer's disease suggest the potential of this approach in identifying therapeutic targets for diseases involving dysregulation of PPS.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Physics, Applied
Thomas C. T. Michaels, Daoyuan Qian, Andela Saric, Michele Vendruscolo, Sara Linse, Tuomas P. J. Knowles
Summary: This Review discusses the general protein self-assembly behavior of amyloid fibrils, which is associated with functional biology and the development of diseases such as Alzheimer and Parkinson diseases. It summarizes recent progress in describing the biophysical features of amyloid self-assembly as a nucleation-and-growth process, highlighting the role of secondary nucleation. The Review also outlines non-classical aspects of aggregate formation and discusses their implications for understanding and modulating protein assembly pathways.
NATURE REVIEWS PHYSICS
(2023)
Article
Multidisciplinary Sciences
Mauricio Aguilar Rangel, Alice Bedwell, Elisa Costanzi, Ross J. Taylor, Rosaria Russo, Goncalo J. L. Bernardes, Stefano Ricagno, Judith Frydman, Michele Vendruscolo, Pietro Sormanni
Summary: The method describes a fragment-based approach to design antibody binding loops and graft them onto antibody scaffolds, providing a starting point for rapidly generating lead antibodies binding to preselected epitopes without the need for a high-resolution input antigen structure.