Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

SAR by kinetics for drug discovery in protein misfolding diseases.

ABSTRACT: To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure-activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (A?), which we then exploit to optimize starting compounds to curtail A? oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of A? oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

SUBMITTER: Chia S

PROVIDER: S-EPMC6187117 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

SAR by kinetics for drug discovery in protein misfolding diseases.

Chia Sean S Habchi Johnny J Michaels Thomas C T TCT Cohen Samuel I A SIA Linse Sara S Dobson Christopher M CM Knowles Tuomas P J TPJ Vendruscolo Michele M

Proceedings of the National Academy of Sciences of the United States of America 20180926 41

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure-activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize startin ...[more]

PMID: 30257937

Similar Datasets

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases.

Project description:The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer's disease (AD), and α-synuclein, linked to Parkinson's disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

| S-EPMC8160836 | biostudies-literature

Integrated Organotypic Slice Cultures and RT-QuIC (OSCAR) Assay: Implications for Translational Discovery in Protein Misfolding Diseases.

Project description:Protein misfolding is a key pathological event in neurodegenerative diseases like prion diseases, synucleinopathies, and tauopathies that are collectively termed protein misfolding disorders. Prions are a prototypic model to study protein aggregation biology and therapeutic development. Attempts to develop anti-prion therapeutics have been impeded by the lack of screening models that faithfully replicate prion diseases and the lack of rapid, sensitive biological screening systems. Therefore, a sensitive model encompassing prion replication and neurotoxicity would be indispensable to the pursuit of intervention strategies. We present an ultra-sensitive screening system coupled to an ex vivo prion organotypic slice culture model to rapidly advance rationale-based high-throughput therapeutic strategies. This hybrid Organotypic Slice Culture Assay coupled with RT-QuIC (OSCAR) permits sensitive, specific and quantitative detection of prions from an infectious slice culture model on a reduced time scale. We demonstrate that the anti-prion activity of test compounds can be readily resolved based on the power and kinetics of seeding activity in the OSCAR screening platform and that the prions generated in slice cultures are biologically active. Collectively, our results imply that OSCAR is a robust model of prion diseases that offers a promising platform for understanding prion proteinopathies and advancing anti-prion therapeutics.

| S-EPMC5324099 | biostudies-literature

Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses.

Project description:Misfolding and extracellular deposition of proteins is the hallmark of a heterogeneous group of conditions collectively termed protein misfolding and deposition diseases or amyloidoses. These include both localized (e.g. Alzheimer's disease, prion diseases, type 2 diabetes mellitus) and systemic amyloidoses. Historically regarded as a group of maladies with limited, even inexistent, therapeutic options, some forms of systemic amyloidoses have recently witnessed a series of unparalleled therapeutic successes, positively impacting on their natural history and sometimes even on their incidence. In this review article we will revisit the most relevant of these accomplishments. Collectively, current evidence converges towards a crucial role of an early and conspicuous reduction or stabilization of the amyloid-forming protein in its native conformation. Such an approach can reduce disease incidence in at risk individuals, limit organ function deterioration, promote organ function recovery, improve quality of life and extend survival in diseased subjects. Therapeutic success achieved in these forms of systemic amyloidoses may guide the research on other protein misfolding and deposition diseases for which effective etiologic therapeutic options are still absent.

| S-EPMC7366848 | biostudies-literature

Gene therapy for misfolding protein diseases of the central nervous system.

Project description:Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. Accordingly, most recent studies aim to prevent protein misfolding and/or aggregation as a strategy to treat these pathologies. For instance, state-of-the-art approaches, such as silencing protein overexpression by means of RNA interference, are being tested with positive outcomes in preclinical models of animals overexpressing the corresponding protein. Therapies designed to treat central nervous system diseases should provide accurate delivery of the therapeutic agent and long-term or chronic expression by means of a nontoxic delivery vehicle. After several years of technical advances and optimization, gene therapy emerges as a promising approach able to fulfill those requirements. In this review we will summarize the latest improvements achieved in gene therapy for central nervous system diseases associated with protein misfolding (e.g., amyotrophic lateral sclerosis, Alzheimer's, Parkinson's, Huntington's, and prion diseases), as well as the most recent approaches in this field to treat these pathologies.

| S-EPMC3701766 | biostudies-literature

Mathematical Modeling of Protein Misfolding Mechanisms in Neurological Diseases: A Historical Overview.

Project description:Protein misfolding refers to a process where proteins become structurally abnormal and lose their specific 3-dimensional spatial configuration. The histopathological presence of misfolded protein (MP) aggregates has been associated as the primary evidence of multiple neurological diseases, including Prion diseases, Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease. However, the exact mechanisms of MP aggregation and propagation, as well as their impact in the long-term patient's clinical condition are still not well understood. With this aim, a variety of mathematical models has been proposed for a better insight into the kinetic rate laws that govern the microscopic processes of protein aggregation. Complementary, another class of large-scale models rely on modern molecular imaging techniques for describing the phenomenological effects of MP propagation over the whole brain. Unfortunately, those neuroimaging-based studies do not take full advantage of the tremendous capabilities offered by the chemical kinetics modeling approach. Actually, it has been barely acknowledged that the vast majority of large-scale models have foundations on previous mathematical approaches that describe the chemical kinetics of protein replication and propagation. The purpose of the current manuscript is to present a historical review about the development of mathematical models for describing both microscopic processes that occur during the MP aggregation and large-scale events that characterize the progression of neurodegenerative MP-mediated diseases.

| S-EPMC5801313 | biostudies-literature

African trypanosomiasis: Synthesis & SAR enabling novel drug discovery of ubiquinol mimics for trypanosome alternative oxidase.

Project description:African trypanosomiasis is a parasitic disease affecting 5000 humans and millions of livestock animals in sub-Saharan Africa every year. Current treatments are limited, difficult to administer and often toxic causing long term injury or death in many patients. Trypanosome alternative oxidase is a parasite specific enzyme whose inhibition by the natural product ascofuranone (AF) has been shown to be curative in murine models. Until now synthetic methods to AF analogues have been limited, this has restricted both understanding of the key structural features required for binding and also how this chemotype could be developed to an effective therapeutic agent. The development of 3 amenable novel synthetic routes to ascofuranone-like compounds is described. The SAR generated around the AF chemotype is reported with correlation to the inhibition of T. b. brucei growth and corresponding selectivity in cytotoxic assessment in mammalian HepG2 cell lines. These methods allow access to greater synthetic diversification and have enabled the synthesis of compounds that have and will continue to facilitate further optimisation of the AF chemotype into a drug-like lead.

| S-EPMC5697954 | biostudies-literature

Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson's Disease: Roads to Biomarker Discovery.

Project description:Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

| S-EPMC8534011 | biostudies-literature

Structural genomics and drug discovery for infectious diseases.

Project description:The application of structural genomics methods and approaches to proteins from organisms causing infectious diseases is making available the three dimensional structures of many proteins that are potential drug targets and laying the groundwork for structure aided drug discovery efforts. There are a number of structural genomics projects with a focus on pathogens that have been initiated worldwide. The Center for Structural Genomics of Infectious Diseases (CSGID) was recently established to apply state-of-the-art high throughput structural biology technologies to the characterization of proteins from the National Institute for Allergy and Infectious Diseases (NIAID) category A-C pathogens and organisms causing emerging, or re-emerging infectious diseases. The target selection process emphasizes potential biomedical benefits. Selected proteins include known drug targets and their homologs, essential enzymes, virulence factors and vaccine candidates. The Center also provides a structure determination service for the infectious disease scientific community. The ultimate goal is to generate a library of structures that are available to the scientific community and can serve as a starting point for further research and structure aided drug discovery for infectious diseases. To achieve this goal, the CSGID will determine protein crystal structures of 400 proteins and protein-ligand complexes using proven, rapid, highly integrated, and cost-effective methods for such determination, primarily by X-ray crystallography. High throughput crystallographic structure determination is greatly aided by frequent, convenient access to high-performance beamlines at third-generation synchrotron X-ray sources.

| S-EPMC2789569 | biostudies-literature

Drug discovery for neglected diseases: molecular target-based and phenotypic approaches.

Project description:Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets.

| S-EPMC3954685 | biostudies-other

(Q)SAR Models of HIV-1 Protein Inhibition by Drug-Like Compounds.

Project description:Despite the achievements of antiretroviral therapy, discovery of new anti-HIV medicines remains an essential task because the existing drugs do not provide a complete cure for the infected patients, exhibit severe adverse effects, and lead to the appearance of resistant strains. To predict the interaction of drug-like compounds with multiple targets for HIV treatment, ligand-based drug design approach is widely applied. In this study, we evaluated the possibilities and limitations of (Q)SAR analysis aimed at the discovery of novel antiretroviral agents inhibiting the vital HIV enzymes. Local (Q)SAR models are based on the analysis of structure-activity relationships for molecules from the same chemical class, which significantly restrict their applicability domain. In contrast, global (Q)SAR models exploit data from heterogeneous sets of drug-like compounds, which allows their application to databases containing diverse structures. We compared the information for HIV-1 integrase, protease and reverse transcriptase inhibitors available in the EBI ChEMBL, NIAID HIV/OI/TB Therapeutics, and Clarivate Analytics Integrity databases as the sources for (Q)SAR training sets. Using the PASS and GUSAR software, we developed and validated a variety of (Q)SAR models, which can be further used for virtual screening of new antiretrovirals in the SAVI library. The developed models are implemented in the freely available web resource AntiHIV-Pred.

| S-EPMC6983201 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data