A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles DOI Creative Commons
Shasha Yao, Yi Wang, Qian Tang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 22, 2024

Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these rely on specific lysosome-trafficking receptors facilitate lysosomal delivery, which may raise resistance concerns due intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), plug-and-play monofunctional degradation that can drag targets into lysosomes for harnesses inherent lysosome-targeting ability certain nanoparticles obviate dependency hook effect. To achieve high modularity programmable target specificity, utilize streptavidin-biotin interaction immobilize antibodies other targeting molecules nanoparticles, through an antibody mounting approach by direct binding. Our study reveals induce efficient diverse therapeutic targets, including membrane proteins, secreted even vesicles. methods but receptors, raising issues. authors MONOTAB, degrades proteins vesicles without dependency.

Language: Английский

Applications of protein ubiquitylation and deubiquitylation in drug discovery DOI Creative Commons
Yilin Chen, Haoan Xue, Jianping Jin

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(5), P. 107264 - 107264

Published: April 5, 2024

The ubiquitin-proteasome system (UPS) is the major machinery mediating specific protein turnover in eukaryotic cells. By ubiquitylating unwanted, damaged, or harmful proteins and driving their degradation, UPS involved many important cellular processes. Several new UPS-based technologies, including molecular glue degraders PROTACs (Proteolysis-targeting chimeras) to promote DUBTACs (deubiquitinase-targeting increase stability, have been developed. specifically inducing interactions between different ubiquitin ligases targeted that are not otherwise related, degrade via system; contrast, by proximity of deubiquitinases, created clear degradable polyubiquitin chains stabilize proteins. In this review, we summarize recent research progress degraders, PROTACs, applications. We discuss immunomodulatory drugs (IMiDs), sulfonamides, CDK-targeting development PROTACs. also introduce principle DUBTAC its Finally, propose a few future directions these three technologies related homeostasis.

Language: Английский

Citations

16
Targeted protein degradation: advances in drug discovery and clinical practice DOI Creative Commons
Guangcai Zhong, Xiaoyu Chang, Weilin Xie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

Citations

14
What influences the activity of Degrader−Antibody conjugates (DACs) DOI
Yaolin Guo,

Xiaoxue Li,

Yang Xie

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 268, P. 116216 - 116216

Published: Feb. 3, 2024

Language: Английский

Citations

8
Expanding the ligand spaces for E3 ligases for the design of protein degraders DOI Creative Commons
Rahman Shah Zaib Saleem, Martin P. Schwalm, Stefan Knapp

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 105, P. 117718 - 117718

Published: April 12, 2024

Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based degraders evolved over past two decades and now established molecular tags that are already in clinical use, well chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for E3 ligases CRBN VHL. The large size human ligase family suggests PROTACs can be by targeting a diversity ligases, some which have restricted expression patterns with potential to design disease- or tissue-specific degraders. Indeed, many ligands been published recently, confirming druggability ligases. This review summarises recent data highlights challenges these molecules into efficient rivalling degrader systems.

Language: Английский

Citations

8
Targeted Protein Degradation: Current and Emerging Approaches for E3 Ligase Deconvolution DOI
Yufeng Xiao, Yaxia Yuan, Yi Liu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: July 9, 2024

Targeted protein degradation (TPD), including the use of proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) to degrade proteins, is an emerging strategy develop novel therapies for cancer beyond. PROTACs or MGDs function by inducing proximity between E3 ligase a interest (POI), leading ubiquitination consequent proteasomal POI. Notably, one major issue in TPD lack ligandable ligases, as current studies predominantly CUL4

Language: Английский

Citations

8
Routes to molecular glue degrader discovery DOI Creative Commons
Yanfen Liu, Jieyun Bai, Dong Li

et al.

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Mechanism of degrader-targeted protein ubiquitinability DOI Creative Commons
Charlotte Crowe, Mark A. Nakasone, Sarah Chandler

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 5, 2024

Abstract Small molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and the potential to tackle previously undrugged targets. Thermodynamically stable kinetically long-lived degrader-mediated ternary complexes can drive faster, more profound durable target degradation, however mechanistic features by which they impact on ubiquitination remain elusive. Here, we solve cryo-EM structures VHL Cullin 2 RING E3 ligase complexed degrader MZ1, protein Brd4 BD2 primed for catalysis its cognate E2-ubiquitin bound. We find that adopts favourable orientation towards E2 active site. In vitro coupled mass spectrometry illuminates patch ubiquitinable lysines one face , Lys456 showing optimal distance geometry nucleophilic attack. Our results demonstrate proficiency MZ1 in directing substrate catalysis, explains favourability ubiquitination, reveals flexibility enzyme capturing sub-optimal lysines. propose model ubiquitinability degrader-recruited targets provides blueprint further rational drug design optimization. One-Sentence Summary Structural assembly PROTAC-mediated complex whole bound structural insights specificity ubiquitination.

Language: Английский

Citations

7
Breaking Bad Proteins—Discovery Approaches and the Road to Clinic for Degraders DOI Creative Commons
Corentin Bouvier, Rachel Lawrence,

Francesca Cavallo

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 578 - 578

Published: March 26, 2024

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding ubiquitin ligase. More generally referred as bifunctional degraders, PROTACs have led the way in field targeted protein (TPD), with several currently undergoing clinical testing. Alongside single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered viable approach for development therapeutics, driven advances rational discovery approaches. This review focuses on drug respect within proteasome system, including analysis mechanistic concepts approaches, an overview current pre-clinical degrader status oncology, neurodegenerative inflammatory disease.

Language: Английский

Citations

7
Trends in surface plasmon resonance biosensing: materials, methods, and machine learning DOI
Daniel D. Stuart, Westley Van Zant, Santino N. Valiulis

et al.

Analytical and Bioanalytical Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

Language: Английский

Citations

6
Mechanism of degrader-targeted protein ubiquitinability DOI Creative Commons
Charlotte Crowe, Mark A. Nakasone, Sarah Chandler

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(41)

Published: Oct. 11, 2024

Small-molecule degraders of disease-driving proteins offer a clinically proven modality with enhanced therapeutic efficacy and potential to tackle previously undrugged targets. Stable long-lived degrader-mediated ternary complexes drive fast profound target degradation; however, the mechanisms by which they affect ubiquitination remain elusive. Here, we show cryo-EM structures VHL Cullin 2 RING E3 ligase degrader MZ1 directing protein Brd4 BD2 toward UBE2R1-ubiquitin, Lys 456 at optimal positioning for nucleophilic attack. In vitro mass spectrometry illuminate patch favorably ubiquitinable lysines on one face , cellular degradation ubiquitinomics confirming importance nearby 368 /Lys 445 identifying “ubiquitination zone.” Our results demonstrate proficiency in substrate catalysis, favorability UBE2R1, flexibility CRL2 capturing suboptimal lysines. We propose model ubiquitinability degrader-recruited targets, providing mechanistic blueprint further rational drug design.

Language: Английский

Citations

5