Therapeutic strategies for identifying small molecules against prion diseases

2022 ◽  
Author(s):  
Elisa Uliassi ◽  
Lea Nikolic ◽  
Maria Laura Bolognesi ◽  
Giuseppe Legname
Keyword(s):  
Small Molecules ◽  
Prion Diseases ◽  
Therapeutic Strategies

scholarly journals COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 993
Author(s):  
Renuka Raman ◽  
Krishna J. Patel ◽  
Kishu Ranjan
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Viral Vector ◽  
Therapeutic Strategies ◽  
Convincing Evidence ◽  
Plasma Therapy ◽  
Therapeutic Monoclonal Antibodies ◽  
Increased Susceptibility

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

scholarly journals Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

2020 ◽  
Vol 13 (7) ◽  
pp. 140
Author(s):  
Sarah Baudet ◽  
Johann Bécret ◽  
Xavier Nicol
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Molecules ◽  
Therapeutic Strategies ◽  
Signaling Cascade ◽  
Molecular Tools ◽  
Pathological Conditions ◽  
Wide Range ◽  
Key Players ◽  
Direct Targeting ◽  
Stem Cell Niches

Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here.

scholarly journals Alteration of RNA Splicing by Small-Molecule Inhibitors of the Interaction between NHP2L1 and U4

2017 ◽  
Vol 23 (2) ◽  
pp. 164-173 ◽  
Author(s):  
Barthelemy Diouf ◽  
Wenwei Lin ◽  
Asli Goktug ◽  
Christy R. R. Grace ◽  
Michael Brett Waddell ◽  
...  
Keyword(s):  
Small Molecules ◽  
Rna Splicing ◽  
High Throughput Screening ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Therapeutic Strategies ◽  
Biological Processes ◽  
Time Resolved Fluorescence ◽  
Time Resolved ◽  
U4 Rna

Splicing is an important eukaryotic mechanism for expanding the transcriptome and proteome, influencing a number of biological processes. Understanding its regulation and identifying small molecules that modulate this process remain a challenge. We developed an assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to detect the interaction between the protein NHP2L1 and U4 RNA, which are two key components of the spliceosome. We used this assay to identify small molecules that interfere with this interaction in a high-throughput screening (HTS) campaign. Topotecan and other camptothecin derivatives were among the top hits. We confirmed that topotecan disrupts the interaction between NHP2L1 and U4 by binding to U4 and inhibits RNA splicing. Our data reveal new functions of known drugs that could facilitate the development of therapeutic strategies to modify splicing and alter gene function.

scholarly journals COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

2021 ◽  
Author(s):  
Renuka Raman ◽  
Krishna J. Patel ◽  
Kishu Ranjan
Keyword(s):  
Immune Response ◽  
Severe Acute Respiratory Syndrome ◽  
Small Molecules ◽  
Human Health ◽  
Viral Vector ◽  
Therapeutic Strategies ◽  
Etiological Agent ◽  
Plasma Therapy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic which has been a topic of major concern to global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7, B.1.351, P1 and, B.1.617., which show in-creased transmissibility and resistance towards vaccines and therapies. Importantly, the likelihood of susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response or comorbidities needs greater attention. Herein, we provide a comprehensive perspective regarding ongoing vaccine (mRNA, protein-based, viral vector based etc.) and therapeutic (mono-clonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

scholarly journals THE USE OF TOFACITINIB FOR TREATMENT PATIENTS WITH PSORIASIS IN CONDITIONS OF THE DERMATOLOGICAL HOSPITAL

2017 ◽  
Vol 20 (4) ◽  
pp. 220-226
Author(s):  
Ella V. Natarova ◽  
N. S Rudneva ◽  
M. S Kuklina ◽  
Ya. Yu Chumakova
Keyword(s):  
Signal Transduction ◽  
Psoriatic Arthritis ◽  
Small Molecules ◽  
Observational Studies ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Local Data ◽  
Janus Kinases ◽  
Short Course ◽  
Intracellular Signal

A growing understanding of the cellular and molecular mechanisms of inflammation in psoriasis and psoriatic arthritis opens the way to the treatment these diseases with the help of new small molecules, associated with the blockade of intracellular signal transduction. Jaqinus®/Xeljanz® (tofacitinib, “Pfizer”) is the first oral inhibitor of Janus kinases for the treatment of chronic moderately severe and severe plaque psoriasiswhich was approved for usage in Russia. The authors also present own local data regarding usage of tofacitinib 10 and 20 mg/day by short course for the treatment group of 13 patients with severe forms of plaque psoriasis in a progressing stage with resistance to prior systemic conventional therapy who were treated at the TDVCD. The efficacy of therapeutic strategies with the use of tofacitinib for patients of the dermatological hospital with the aim of improving and stabilizing of acute process is shown. Further prospective and observational studies to refine the dosing and safety profile of this group of drugs are needed.

scholarly journals Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations

2019 ◽  
Vol 20 (24) ◽  
pp. 6274 ◽  
Author(s):  
Ananya Samanta ◽  
Katarina Stingl ◽  
Susanne Kohl ◽  
Jessica Ries ◽  
Joshua Linnert ◽  
...  
Keyword(s):  
Small Molecules ◽  
Nonsense Mutation ◽  
Usher Syndrome ◽  
Premature Termination Codon ◽  
Therapeutic Strategies ◽  
Published Data ◽  
Genetic Defects ◽  
Retinal Diseases ◽  
Nonsense Mutations ◽  
Healthy Donors

The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs; TRIDs) have the potential to mediate the read-through of nonsense mutations by inducing expression of the full-length protein. We provide novel data on the read-through efficacy of Ataluren on a nonsense mutation in the Usher syndrome gene USH2A that causes deaf-blindness in humans. We demonstrate Ataluren´s efficacy in both transiently USH2AG3142*-transfected HEK293T cells and patient-derived fibroblasts by restoring USH2A protein expression. Furthermore, we observed enhanced ciliogenesis in patient-derived fibroblasts after treatment with TRIDs, thereby restoring a phenotype that is similar to that found in healthy donors. In light of recent findings, we validated Ataluren´s efficacy to induce read-through on a nonsense mutation in USH2A-related IRD. In line with published data, our findings support the use of patient-derived fibroblasts as a platform for the validation of preclinical therapies. The excellent biocompatibility combined with sustained read-through efficacy makes Ataluren an ideal TRID for treating nonsense mutations based IRDs.

scholarly journals Discovery of 2-Aminothiazoles as Potent Antiprion Compounds

2009 ◽  
Vol 84 (7) ◽  
pp. 3408-3412 ◽  
Author(s):  
Sina Ghaemmaghami ◽  
Barnaby C. H. May ◽  
Adam R. Renslo ◽  
Stanley B. Prusiner
Keyword(s):  
Small Molecules ◽  
Prion Diseases ◽  
Neuroblastoma Cell ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lead Compounds ◽  
Primary Screening ◽  
Structure Activity ◽  
Neuroblastoma Cell Lines ◽  
Efficacy Studies

ABSTRACT Prion diseases are fatal, untreatable neurodegenerative diseases caused by the accumulation of the misfolded, infectious isoform of the prion protein (PrP), termed PrPSc. In an effort to identify novel inhibitors of prion formation, we utilized a high-throughput enzyme-linked immunosorbent assay (ELISA) to evaluate PrPSc reduction in prion-infected neuroblastoma cell lines (ScN2a). We screened a library of ∼10,000 diverse small molecules in 96-well format and identified 121 compounds that reduced PrPSc levels at a concentration of 5 μM. Four chemical scaffolds were identified as potential candidates for chemical optimization based on the presence of preliminary structure-activity relationships (SAR) derived from the primary screening data. A follow-up analysis of a group of commercially available 2-aminothiazoles showed this class as generally active in ScN2a cells. Our results establish 2-aminothiazoles as promising candidates for efficacy studies of animals and validate our drug discovery platform as a viable strategy for the identification of novel lead compounds with antiprion properties.

scholarly journals Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Roxine Staats ◽  
Thomas C. T. Michaels ◽  
Patrick Flagmeier ◽  
Sean Chia ◽  
Robert I. Horne ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Unmet Need ◽  
Screening Strategy ◽  
Therapeutic Strategies ◽  
Selection Strategy ◽  
Oligomer Formation ◽  
Selection Parameter ◽  
Flavone Derivatives ◽  
Compound Selection

AbstractThe aggregation of α-synuclein is a central event in Parkinsons’s disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation.

scholarly journals KOMBAT: Knowledgebase of Microbes’ Battling Agents for Therapeutics

2021 ◽  
Author(s):  
Anasuya Bhargav ◽  
Srijanee Gupta ◽  
Surabhi Seth ◽  
Sweety James ◽  
Firdaus Fatima ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Small Molecules ◽  
Safety Information ◽  
Antibiotic Resistance Genes ◽  
Therapeutic Strategies ◽  
Microbial Pathogens ◽  
Effective Prevention ◽  
Natural Tendency ◽  
Incomplete Treatment ◽  
New Strategies

Antimicrobial resistance (AMR) is one of the top 10 threats affecting global health. AMR defeats the effective prevention and treatment of infections caused by microbial pathogens including bacteria, parasites, viruses and fungi (WHO). Microbial pathogens have natural tendency to evolve and mutate over time resulting in AMR strains. The set of genes involved in antibiotic resistance also termed as “antibiotic resistance genes” (ARGs) spread through species by lateral gene transfer thereby causing global dissemination. While this biological mechanism is prevalent in the spread of AMR, human methods also augment through various mechanisms such as over prescription, incomplete treatment, environmental waste etc. A considerable portion of scientific community is engrossed in AMR related work trying to discover novel therapeutic solutions for tackling resistant pathogens. Comprehensive inspection of the literature shows that diverse therapeutic strategies have evolved over recent years. Collectively, these therapeutic strategies include novel small molecules, newly identified antimicrobial peptides, bacteriophages, phytochemicals, nanocomposites, novel phototherapy against bacteria, fungi and virus. In this work we have developed a comprehensive knowledgebase by collecting alternative antimicrobial therapeutic strategies from literature data. We have used subjective approach for datamining new strategies resulting in broad coverage of entities and subsequently add objective data like entity name, potency, safety information etc. The extracted data was organized KOMBAT (Knowledgebase Of Microbes’ Battling Agents for Therapeutics). A lot of these data are tested against AMR pathogens. We envision that this database will be noteworthy for developing future therapeutics against resistant pathogens. The database can be accessed through http://kombat.igib.res.in/.

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