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  1. Article ; Online: Diversity-Oriented Synthesis (DOS) of On-DNA Peptidomimetics from Acid-Derived Phosphonium Ylides.

    Krishna Sunkari, Yashoda / Kumar Siripuram, Vijay / Flajolet, Marc

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2023  Volume 29, Issue 11, Page(s) e202203037

    Abstract: The DNA-encoded library (DEL) technology represents a revolutionary drug-discovery tool with unprecedented screening power originating from the association of combinatorial chemistry and DNA barcoding. The chemical diversity of DELs and its chemical ... ...

    Abstract The DNA-encoded library (DEL) technology represents a revolutionary drug-discovery tool with unprecedented screening power originating from the association of combinatorial chemistry and DNA barcoding. The chemical diversity of DELs and its chemical space will be further expanded as new DNA-compatible reactions are introduced. This work introduces the use of DOS in the context of on-DNA peptidomimetics. Wittig olefination of aspartic acid-derived on-DNA Wittig ylide, combined with a broad substrate scope of aldehydes, led to formation of on-DNA
    MeSH term(s) Peptidomimetics ; Aldehydes/chemistry ; Ketones
    Chemical Substances Peptidomimetics ; Aldehydes ; Ketones
    Language English
    Publishing date 2023-01-18
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.202203037
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  2. Article ; Online: Reversible and Fully Controllable Generation of Organo-Soluble DNA (osDNA).

    Siripuram, Vijay Kumar / Sunkari, Yashoda Krishna / Ma, Fei / Nguyen, Thu-Lan / Flajolet, Marc

    ACS omega

    2024  Volume 9, Issue 13, Page(s) 14771–14780

    Abstract: The present work describes a complete and reversible transformation of DNA's properties allowing solubilization in organic solvents and subsequent chemical modifications that are otherwise not possible in an aqueous medium. Organo-soluble DNA (osDNA) ... ...

    Abstract The present work describes a complete and reversible transformation of DNA's properties allowing solubilization in organic solvents and subsequent chemical modifications that are otherwise not possible in an aqueous medium. Organo-soluble DNA (osDNA) moieties are generated by covalently linking a dsDNA fragment to a polyether moiety with a built-in mechanism, rendering the process perfectly reversible and fully controllable. The precise removal of the polyether moiety frees up the initial DNA fragment, unaltered, both in sequence and nature. The solubility of osDNA was confirmed in six organic solvents of decreasing polarity and six types of osDNAs. As a proof of concept, in the context of DNA-encoded library (DEL) technology, an amidation reaction was successfully performed on osDNA in 100% DMSO. The development of osDNA opens up entirely new avenues for any DNA applications that could benefit from working in nonaqueous solutions, including chemical transformations.
    Language English
    Publishing date 2024-03-19
    Publishing country United States
    Document type Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.3c06755
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  3. Article ; Online: Impact of organic chemistry conditions on DNA durability in the context of DNA-encoded library technology.

    Sunkari, Yashoda Krishna / Nguyen, Thu-Lan / Siripuram, Vijay Kumar / Flajolet, Marc

    iScience

    2023  Volume 26, Issue 9, Page(s) 107573

    Abstract: High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome ... ...

    Abstract High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome limitations and DNA durability (e.g., depurination, loss of phosphate groups, adduct formation) is compromised in numerous organic chemistry conditions that require empirical testing. An atlas of reaction conditions (temperature, pH, solvent/buffer, ligands, oxidizing reagents, catalysts, scavengers in function of time) that have been systematically tested in multiple combinations, indicates precisely limits useful for DEL construction. More importantly, this approach could be used broadly to effectively evaluate DNA-compatibility of any novel on-DNA chemical reaction, and it is compatible with different molecular methodologies. This atlas and the general approach presented, by allowing novel reaction conditions to be performed in presence of DNA, should greatly help in expanding the DEL chemical space as well as any field involving DNA durability.
    Language English
    Publishing date 2023-08-09
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2023.107573
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  4. Article: The protein kinase CK1: Inhibition, activation, and possible allosteric modulation.

    Sunkari, Yashoda Krishna / Meijer, Laurent / Flajolet, Marc

    Frontiers in molecular biosciences

    2022  Volume 9, Page(s) 916232

    Abstract: Protein kinases play a vital role in biology and deregulation of kinases is implicated in numerous diseases ranging from cancer to neurodegenerative diseases, making them a major target class for the pharmaceutical industry. However, the high degree of ... ...

    Abstract Protein kinases play a vital role in biology and deregulation of kinases is implicated in numerous diseases ranging from cancer to neurodegenerative diseases, making them a major target class for the pharmaceutical industry. However, the high degree of conservation that exists between ATP-binding sites among kinases makes it difficult for current inhibitors to be highly specific. In the context of neurodegeneration, several groups including ours, have linked different kinases such as CK1 and Alzheimer's disease for example. Strictly CK1-isoform specific regulators do not exist and known CK1 inhibitors are inhibiting the enzymatic activity, targeting the ATP-binding site. Here we review compounds known to target CK1, as well as other inhibitory types that could benefit CK1. We introduce the DNA-encoded library (DEL) technology that might represent an interesting approach to uncover allosteric modulators instead of ATP competitors. Such a strategy, taking into account known allosteric inhibitors and mechanisms, might help designing modulators that are more specific towards a specific kinase, and in the case of CK1, toward specific isoforms.
    Language English
    Publishing date 2022-08-24
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2814330-9
    ISSN 2296-889X
    ISSN 2296-889X
    DOI 10.3389/fmolb.2022.916232
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  5. Article: DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries.

    Siripuram, Vijay Kumar / Sunkari, Yashoda Krishna / Nguyen, Thu-Lan / Flajolet, Marc

    Frontiers in chemistry

    2022  Volume 10, Page(s) 894603

    Abstract: An efficient method for the C-C bond formation via water soluble ... ...

    Abstract An efficient method for the C-C bond formation via water soluble Na
    Language English
    Publishing date 2022-06-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2711776-5
    ISSN 2296-2646
    ISSN 2296-2646
    DOI 10.3389/fchem.2022.894603
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  6. Article ; Online: High-power screening (HPS) empowered by DNA-encoded libraries.

    Sunkari, Yashoda Krishna / Siripuram, Vijay Kumar / Nguyen, Thu-Lan / Flajolet, Marc

    Trends in pharmacological sciences

    2021  Volume 43, Issue 1, Page(s) 4–15

    Abstract: The world is totally dependent on medications. As science progresses, new, better, and cheaper drugs are needed more than ever. The pharmaceutical industry has been predominantly dependent on high-throughput screening (HTS) for the past three decades. ... ...

    Abstract The world is totally dependent on medications. As science progresses, new, better, and cheaper drugs are needed more than ever. The pharmaceutical industry has been predominantly dependent on high-throughput screening (HTS) for the past three decades. Considering that the discovery rate has been relatively constant, can one hope for a much-needed sudden trend uptick? DNA-encoded libraries (DELs) and similar technologies, that have several orders of magnitude more screening power than HTS, and that we propose to group together under the umbrella term of high-power screening (HPS), are very well positioned to do exactly that. HPS also offers novel screening options such as parallel screening, ex vivo and in vivo screening, as well as a new path to druggable alternatives such as proteolysis targeting chimeras (PROTACs). Altogether, HPS unlocks novel powerful drug discovery avenues.
    MeSH term(s) DNA ; Drug Discovery ; Drug Industry ; High-Throughput Screening Assays ; Humans ; Small Molecule Libraries/pharmacology
    Chemical Substances Small Molecule Libraries ; DNA (9007-49-2)
    Language English
    Publishing date 2021-11-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 282846-7
    ISSN 1873-3735 ; 0165-6147
    ISSN (online) 1873-3735
    ISSN 0165-6147
    DOI 10.1016/j.tips.2021.10.008
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  7. Article ; Online: Paul Greengard: A persistent desire to comprehend the brain, and also to fix it.

    Flajolet, Marc / Nguyen, Thu Lan / Siripuram, Vijay Kumar / Sunkari, Yashoda Krishna

    Advances in pharmacology (San Diego, Calif.)

    2020  Volume 90, Page(s) 1–18

    Abstract: Paul Greengard's name is and will remain profoundly associated with Neuroscience, with brain signaling and chemical transmission, with Parkinson's and Alzheimer's diseases, with fundamental discoveries and solving paradoxes, but much less perhaps with ... ...

    Abstract Paul Greengard's name is and will remain profoundly associated with Neuroscience, with brain signaling and chemical transmission, with Parkinson's and Alzheimer's diseases, with fundamental discoveries and solving paradoxes, but much less perhaps with drug discovery. This should not be mistaken as disdain. Paul in fact did contemplate developing therapeutic avenues to actually treat brain diseases much more than it is known, perhaps during his entire career, and certainly over the last two decades. As a matter of fact, he did more than contemplate it, he directly and indirectly contributed in the development of treatments for neurological diseases and disorders. Paul's impact on fundamental aspects of the brain has been so gargantuan that any other aspect of Paul's life will have difficulty to shine. It is precisely this less known aspect of Paul's career that will be covered in this review. We will discover how Paul very early on moved away from biophysics to avoid working on nuclear weapons and instead started his career in the pharmacological spheres of a large pharmaceutical company.
    MeSH term(s) Animals ; Brain/physiology ; Brain Diseases/pathology ; Drug Approval ; Drug Development ; Humans ; Molecular Targeted Therapy ; Weapons
    Language English
    Publishing date 2020-10-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1557-8925
    ISSN (online) 1557-8925
    DOI 10.1016/bs.apha.2020.09.008
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  8. Article ; Online: Comme un poisson dans l'eau - Hommage à Oliver Sacks (1933-2015) - Ou de l'intérêt d'offrir aux enfants la possibilité de se familiarise avec l'élément aquatique dès leur plus jeune âge.

    Fourel, Geneviève / Flajolet, Marc

    Medecine sciences : M/S

    2016  Volume 32, Issue 4, Page(s) 408–411

    Title translation Just like a fish in water - Oliver Sacks (1933-2015): an hommage - On the importance of swimming from infancy.
    MeSH term(s) Age Factors ; Animals ; Fishes/physiology ; History, 20th Century ; History, 21st Century ; Humans ; Infant ; Neurology/history ; Publications ; Swimming/physiology ; Swimming/psychology ; Water ; Writing/history
    Chemical Substances Water (059QF0KO0R)
    Language French
    Publishing date 2016-04
    Publishing country France
    Document type Bibliography ; Biography ; Historical Article ; Journal Article ; Portraits
    ZDB-ID 632733-3
    ISSN 1958-5381 ; 0767-0974
    ISSN (online) 1958-5381
    ISSN 0767-0974
    DOI 10.1051/medsci/20163204020
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    Zs.B 2872: Show issues Location:
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  9. Article ; Online: A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.

    Rodriguez-Rodriguez, Patricia / Arroyo-Garcia, Luis Enrique / Tsagkogianni, Christina / Li, Lechuan / Wang, Wei / Végvári, Ákos / Salas-Allende, Isabella / Plautz, Zakary / Cedazo-Minguez, Angel / Sinha, Subhash C / Troyanskaya, Olga / Flajolet, Marc / Yao, Vicky / Roussarie, Jean-Pierre

    Brain : a journal of neurology

    2024  

    Abstract: Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help ... ...

    Abstract Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early AD. The existence of a cell-autonomous mechanism linking AD pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in AD.
    Language English
    Publishing date 2024-03-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awae051
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    Ui II Zs.26: Show issues Location:
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  10. Article ; Online: Rational Development of a Small-Molecule Activator of CK1γ2 That Decreases C99 and Beta-Amyloid Levels.

    Bustos, Victor Hugo / Sunkari, Yashoda Krishna / Sinha, Anjana / Pulina, Maria / Bispo, Ashley / Hopkins, Maya / Lam, Alison / Kriegsman, Sydney F / Mui, Emily / Chang, Emily / Jedlicki, Ana / Rosenthal, Hannah / Flajolet, Marc / Sinha, Subhash C

    ACS chemical biology

    2023  Volume 19, Issue 1, Page(s) 37–47

    Abstract: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aβ levels have shown limited ...

    Abstract Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aβ levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aβ levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aβ levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aβ levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aβ concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.
    MeSH term(s) Humans ; Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/drug therapy ; Brain/metabolism
    Chemical Substances Amyloid beta-Protein Precursor ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Amyloid beta-Peptides
    Language English
    Publishing date 2023-12-11
    Publishing country United States
    Document type Journal Article
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.3c00425
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