LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 131

Search options

  1. Article: Proximity-Based Modalities for Biology and Medicine.

    Liu, Xingui / Ciulli, Alessio

    ACS central science

    2023  Volume 9, Issue 7, Page(s) 1269–1284

    Abstract: Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high ... ...

    Abstract Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.
    Language English
    Publishing date 2023-07-14
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2374-7943
    ISSN 2374-7943
    DOI 10.1021/acscentsci.3c00395
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  2. Article ; Online: Ternary Complex-Templated Dynamic Combinatorial Chemistry for the Selection and Identification of Homo-PROTACs.

    Diehl, Claudia J / Salerno, Alessandra / Ciulli, Alessio

    Angewandte Chemie (International ed. in English)

    2024  , Page(s) e202319456

    Abstract: Dynamic combinatorial chemistry (DCC) leverages a reversible reaction to generate compound libraries from constituting building blocks under thermodynamic control. The position of this equilibrium can be biased by addition of a target macromolecule ... ...

    Abstract Dynamic combinatorial chemistry (DCC) leverages a reversible reaction to generate compound libraries from constituting building blocks under thermodynamic control. The position of this equilibrium can be biased by addition of a target macromolecule towards enrichment of bound ligands. While DCC has been applied to select ligands for a single target protein, its application to identifying chimeric molecules inducing proximity between two proteins is unprecedented. In this proof-of-concept study, we develop a DCC approach to select bifunctional proteolysis targeting chimeras (PROTACs) based on their ability to stabilize the ternary complex. We focus on VHL-targeting Homo-PROTACs as model system, and show that the formation of a VHL2:Homo-PROTAC ternary complex reversibly assembled using thiol-disulfide exchange chemistry leads to amplification of potent VHL Homo-PROTACs with degradation activities which correlated well with their biophysical ability to dimerize VHL. Ternary complex templated dynamic combinatorial libraries allowed identification of novel Homo-PROTAC degraders. We anticipate future applications of ternary-complex directed DCC to early PROTAC screenings and expansion to other proximity-inducing modalities beyond PROTACs.
    Language English
    Publishing date 2024-04-16
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202319456
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  3. Article ; Online: DUB be good to me.

    Liu, Xingui / Ciulli, Alessio

    Nature chemical biology

    2022  Volume 18, Issue 4, Page(s) 358–359

    MeSH term(s) Amino Acid Sequence ; Chimera/metabolism ; Deubiquitinating Enzymes/metabolism ; Endopeptidases/metabolism
    Chemical Substances Endopeptidases (EC 3.4.-) ; Deubiquitinating Enzymes (EC 3.4.19.12)
    Language English
    Publishing date 2022-02-24
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-022-00978-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 6251: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 90: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  4. Article ; Online: Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.

    Diehl, Claudia J / Ciulli, Alessio

    Chemical Society reviews

    2022  Volume 51, Issue 19, Page(s) 8216–8257

    Abstract: The von Hippel-Lindau (VHL) Cullin RING E3 ligase is an essential enzyme in the ubiquitin-proteasome system that recruits substrates such as the hypoxia inducible factor for ubiquitination and subsequent proteasomal degradation. The ubiquitin-proteasome ... ...

    Abstract The von Hippel-Lindau (VHL) Cullin RING E3 ligase is an essential enzyme in the ubiquitin-proteasome system that recruits substrates such as the hypoxia inducible factor for ubiquitination and subsequent proteasomal degradation. The ubiquitin-proteasome pathway can be hijacked toward non-native neo-substrate proteins using proteolysis targeting chimeras (PROTACs), bifunctional molecules designed to simultaneously bind to an E3 ligase and a target protein to induce target ubiquitination and degradation. The availability of high-quality small-molecule ligands with good binding affinity for E3 ligases is fundamental for PROTAC development. Lack of good E3 ligase ligands as starting points to develop PROTAC degraders was initially a stumbling block to the development of the field. Herein, the journey towards the design of small-molecule ligands binding to VHL is presented. We cover the structure-based design of VHL ligands, their application as inhibitors in their own right, and their implementation into rationally designed, potent PROTAC degraders of various target proteins. We highlight the key findings and learnings that have provided strong foundations for the remarkable development of targeted protein degradation, and that offer a blueprint for designing new ligands for E3 ligases beyond VHL.
    MeSH term(s) Cullin Proteins ; Ligands ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/metabolism ; Von Hippel-Lindau Tumor Suppressor Protein/chemistry ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism
    Chemical Substances Cullin Proteins ; Ligands ; Ubiquitin ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2022-10-03
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1472875-8
    ISSN 1460-4744 ; 0306-0012
    ISSN (online) 1460-4744
    ISSN 0306-0012
    DOI 10.1039/d2cs00387b
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  5. Article ; Online: Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory.

    Cowan, Angus D / Ciulli, Alessio

    Annual review of biochemistry

    2022  Volume 91, Page(s) 295–319

    Abstract: Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to ... ...

    Abstract Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin-proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated and degraded. This review focuses on the structural determinants of E3 ligase recruitment of natural substrates and neo-substrates obtained through monovalent molecular glues and bivalent proteolysis-targeting chimeras. We use structures to illustrate the different types of substrate recognition and assess the basis for neo-protein-protein interactions in ternary complex structures. The emerging structural and mechanistic complexity is reflective of the diverse physiological roles of protein ubiquitination. This molecular insight is also guiding the application of structure-based design approaches to the development of new and existing degraders as chemical tools and therapeutics.
    MeSH term(s) Proteins/metabolism ; Proteolysis ; Substrate Specificity ; Ubiquitin/genetics ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Chemical Substances Proteins ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2022-03-23
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 207924-0
    ISSN 1545-4509 ; 0066-4154
    ISSN (online) 1545-4509
    ISSN 0066-4154
    DOI 10.1146/annurev-biochem-032620-104421
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.209: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  6. Article ; Online: Crystallization of VHL-based PROTAC-induced ternary complexes.

    Wijaya, Andre J / Farnaby, William / Ciulli, Alessio

    Methods in enzymology

    2023  Volume 681, Page(s) 241–263

    Abstract: X-ray crystal structures of PROTAC-induced ternary complexes provide invaluable insights into the critical species underpinning PROTAC mode of action, explain protein degradation selectivity profiles, and can guide rational degrader design. Nevertheless, ...

    Abstract X-ray crystal structures of PROTAC-induced ternary complexes provide invaluable insights into the critical species underpinning PROTAC mode of action, explain protein degradation selectivity profiles, and can guide rational degrader design. Nevertheless, crystallization of the ternary complexes formed by PROTACs remains an important bottleneck in employing this method. This is mainly due to the potential flexibility and heterogeneity that is inherent to a non-native protein-protein complex mediated by a small molecule, which together can hamper crystallization of the desired species. To overcome this limitation, selecting PROTAC compounds that enable the formation of stable, high-affinity and preferably cooperative ternary complexes in stoichiometric amount is, in our experience, critical to the success of co-crystallization studies. In this chapter, examples of stable PROTAC-mediated ternary complexes are illustrated. Learnings from biophysical & biochemical data are used as a guideline in achieving the highest "crystallizability" of ternary complexes. A case study of VHL-based SMARCA2 PROTAC degrader ternary complex crystallization is described. The procedure includes over-expression and purification of the E3 ligase and target protein, forming (and sometimes isolating) the ternary complex, and crystallizing it. The protocols can be applied for other combinations of E3 ligase, PROTAC and target protein.
    MeSH term(s) Proteolysis Targeting Chimera ; Crystallization ; Proteolysis ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Proteolysis Targeting Chimera ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2023-01-09
    Publishing country United States
    Document type Journal Article
    ISSN 1557-7988
    ISSN (online) 1557-7988
    DOI 10.1016/bs.mie.2022.10.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  7. Article ; Online: Editorial overview: Hot targets and new modalities.

    Ciulli, Alessio / Wertz, Ingrid E

    Current opinion in chemical biology

    2021  Volume 62, Page(s) A1–A3

    MeSH term(s) Antineoplastic Agents/metabolism ; Carrier Proteins/metabolism ; Cytokines/metabolism ; Humans ; Immunotherapy ; Neoplasms/metabolism ; Neoplasms/therapy ; Receptor Protein-Tyrosine Kinases/metabolism ; Sialic Acid Binding Immunoglobulin-like Lectins/metabolism ; Tumor Microenvironment
    Chemical Substances Antineoplastic Agents ; Carrier Proteins ; Cytokines ; Sialic Acid Binding Immunoglobulin-like Lectins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
    Language English
    Publishing date 2021-06-08
    Publishing country England
    Document type Editorial ; Introductory Journal Article
    ZDB-ID 1439176-4
    ISSN 1879-0402 ; 1367-5931
    ISSN (online) 1879-0402
    ISSN 1367-5931
    DOI 10.1016/j.cbpa.2021.04.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 4986: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  8. Article ; Online: Target validation: Switching domains.

    Ciulli, Alessio

    Nature chemical biology

    2016  Volume 12, Issue 9, Page(s) 659–660

    Language English
    Publishing date 2016-08-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/nchembio.2154
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 6251: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 90: Show issues

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  9. Article ; Online: Stereoselective synthesis of allele-specific BET inhibitors.

    Bond, Adam G / Testa, Andrea / Ciulli, Alessio

    Organic & biomolecular chemistry

    2022  Volume 18, Issue 38, Page(s) 7533–7539

    Abstract: Developing stereoselective synthetic routes that are efficient and cost-effective allows easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) domain proteins, ... ...

    Abstract Developing stereoselective synthetic routes that are efficient and cost-effective allows easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) domain proteins, Brd2, Brd3, Brd4 and BrdT, required a wasteful, late-stage alkylation step and expensive chiral separation. To circumvent these limitations, we developed a route based on stereocontrolled alkylation of an N-Pf protected aspartic acid derivative that was used in a divergent, racemisation-free protocol to yield structurally diverse and enantiopure triazolodiazepines. With this approach, we synthesized bumped thienodiazepine-based BET inhibitor, ET-JQ1-OMe, in five steps and 99% ee without the need for chiral chromatography. Exquisite selectivity of ET-JQ1-OMe for Leu-Ala and Leu-Val mutants over wild-type bromodomain was established by isothermal titration calorimetry and X-ray crystallography. Our new approach provides unambiguous chemical evidence for the absolute stereochemistry of the active, allele-specific BET inhibitors and a viable route that will open wider access to this compound class.
    MeSH term(s) Nuclear Proteins
    Chemical Substances BRDT protein, human ; Nuclear Proteins
    Language English
    Publishing date 2022-01-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 2097583-1
    ISSN 1477-0539 ; 1477-0520
    ISSN (online) 1477-0539
    ISSN 1477-0520
    DOI 10.1039/d0ob01165g
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

  10. Article ; Online: Targeting epigenetic modulators using PROTAC degraders: Current status and future perspective.

    Webb, Thomas / Craigon, Conner / Ciulli, Alessio

    Bioorganic & medicinal chemistry letters

    2022  Volume 63, Page(s) 128653

    Abstract: Epigenetic modulators perform critical functions in gene expression for rapid adaption to external stimuli and are prevalent in all higher-order organisms. The establishment of a link between dysregulation of epigenetic processes and disease pathogenesis, ...

    Abstract Epigenetic modulators perform critical functions in gene expression for rapid adaption to external stimuli and are prevalent in all higher-order organisms. The establishment of a link between dysregulation of epigenetic processes and disease pathogenesis, particularly in cancer, has led to much interest in identifying drug targets. This prompted the development of small molecule inhibitors, primarily in haematological malignancies. While there have been epigenetic-targeting drugs to receive FDA approval for the treatment of cancers, many suffer from limited applicability, toxicity and the onset of drug resistance, as our understanding of the biology remains incomplete. The recent advent of genome-wide RNAi and CRISPR screens has shed new light on loss of specific proteins causing vulnerabilities of specific cancer types, highlighting the potential for exploiting synthetic lethality as a therapeutic approach. However, small molecule inhibitors have largely been unable to recapitulate phenotypic effects observed using genome-wide knockdown approaches. This mechanistic disconnect and gap are set to be addressed by targeted protein degradation. Degraders such as PROTACs targeting epigenetic proteins recapitulate CRISPR mediated genetic knockdown at the post-translational level and therefore can better exploit target druggability. Here, we review the current landscape of epigenetic drug discovery, the rationale behind and progress made in the development of PROTAC degraders, and look at future perspectives for the field.
    MeSH term(s) Humans ; Drug Discovery ; Epigenesis, Genetic ; Neoplasms/drug therapy ; Proteolysis
    Language English
    Publishing date 2022-03-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2022.128653
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

    In stock of ZB MED Cologne/Königswinter

    Zs.A 3203: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

To top