An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses DOI Creative Commons
Linjuan Wu, Liming Zhang,

Shengyong Feng

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(16)

Опубликована: Апрель 9, 2024

Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions infections annually. The single-stranded RNA genome is translated into a polyprotein, which cleaved equally individual functional proteins. While structural proteins are packaged progeny virions released, most the nonstructural remain intracellular could become cytotoxic if accumulated over time. However, mechanism by maintained at levels optimal for cellular fitness viral replication remains unknown. Here, we identified that ubiquitin E3 ligase HRD1 essential in both mammalian hosts mosquitoes. directly interacts with flavivirus NS4A ubiquitylates conserved lysine residue ER-associated degradation. This avoids excessive accumulation NS4A, otherwise interrupts expression processed ER. Furthermore, small-molecule inhibitor named LS-102 effectively DENV2 infection mice Aedes aegypti mosquitoes, significantly disturbs DENV transmission from infected to mosquitoes owing reduced viremia. Taken together, this study demonstrates have evolved sophisticated exploit ubiquitination system balance homeostasis their own advantage provides potential therapeutic target interrupt transmission.

Язык: Английский

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic DOI Creative Commons
Janet M. Sasso,

Rumiana Tenchov,

Dasheng Wang

и другие.

Biochemistry, Год журнала: 2022, Номер 62(3), С. 601 - 623

Опубликована: Июль 20, 2022

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential treating diseases such as cancer and infectious, inflammatory, neurodegenerative diseases, especially those with "undruggable" pathogenic targets. With recent rise of "molecular glue" type degraders, which tighten simplify connection an E3 ligase ubiquitination subsequent degradation, new therapies unmet medical needs are being designed developed. Here we use data from CAS Content Collection publication landscape research on targeted degraders provide insights into these molecules, special focus molecular glues. We also outline advantages glues summarize advances in practices glue degraders. further thorough review candidates through recruitment. Finally, highlight progression pipelines their diseases. Overall, our paper provides comprehensive reference support future development medicine.

Язык: Английский

Процитировано

107
Small-molecule discovery through DNA-encoded libraries DOI
Alexander A. Peterson, David R. Liu

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(9), С. 699 - 722

Опубликована: Июнь 16, 2023

Язык: Английский

Процитировано

91
Small molecule inhibitors targeting the cancers DOI Creative Commons
Guihong Liu, Tao Chen, Xin Zhang

и другие.

MedComm, Год журнала: 2022, Номер 3(4)

Опубликована: Окт. 13, 2022

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.

Язык: Английский

Процитировано

87
Targeted protein degradation via intramolecular bivalent glues DOI Creative Commons
Oliver Hsia, Matthias Hinterndorfer, Angus D. Cowan

и другие.

Nature, Год журнала: 2024, Номер 627(8002), С. 204 - 211

Опубликована: Фев. 21, 2024

Abstract Targeted protein degradation is a pharmacological modality that based on the induced proximity of an E3 ubiquitin ligase and target to promote ubiquitination proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed two separate moieties individually bind ligase, or molecular glues monovalently 1–4 . Here, using orthogonal genetic screening, biophysical characterization structural reconstitution, we investigate mechanism action bifunctional degraders BRD2 BRD4, termed intramolecular bivalent (IBGs), find instead connecting in trans as PROTACs do, they simultaneously engage connect adjacent domains cis conformational change ‘glues’ BRD4 ligases DCAF11 DCAF16, leveraging intrinsic target–ligase affinities do not translate absence compound. Structural insights into ternary BRD4–IBG1–DCAF16 complex guided rational design improved low picomolar potency. We thus introduce new targeted degradation, which works by bridging enhance surface complementarity with for productive

Язык: Английский

Процитировано

74
Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation DOI Creative Commons
Ryan P. Wurz, Huan Rui,

Ken Dellamaggiore

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 13, 2023

Abstract Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design PROTACs is challenging; multiple steps involved in PROTAC-induced make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and by employing von Hippel–Lindau (VHL) recruiting for two different target proteins, SMARCA2 BRD4. Ternary-complex attributes activity parameters are evaluated varying components PROTAC’s architecture. Ternary binding affinity cooperativity correlates well with potency initial rates degradation. Additionally, develop ternary-complex structure modeling workflow calculate total buried surface area at interface, which agreement measured affinity. Our findings predictive framework guide potent degraders.

Язык: Английский

Процитировано

51
Proteome-scale discovery of protein degradation and stabilization effectors DOI
Juline Poirson, Hanna Cho,

Akashdeep Dhillon

и другие.

Nature, Год журнала: 2024, Номер 628(8009), С. 878 - 886

Опубликована: Март 20, 2024

Язык: Английский

Процитировано

24
A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction DOI
Pamela Y. Ting, Sneha Borikar,

John Ryan Kerrigan

и другие.

Science, Год журнала: 2024, Номер 385(6704), С. 91 - 99

Опубликована: Июль 4, 2024

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate complications and has been intently pursued. However, safe effective small-molecule inducers HbF remain elusive. We report the discovery dWIZ-1 dWIZ-2, molecular glue degraders WIZ transcription factor that robustly induce erythroblasts. Phenotypic screening cereblon (CRBN)-biased chemical library revealed as previously unknown repressor HbF. degradation mediated by recruitment WIZ(ZF7) CRBN dWIZ-1, resolved crystallography ternary complex. Pharmacological was well tolerated induced humanized mice cynomolgus monkeys. These findings establish globally accessible therapeutic strategy for SCD.

Язык: Английский

Процитировано

16
UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors DOI Creative Commons
Megan J. R. Yeo, Olivia Zhang, Xiaowen Xie

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

Abstract UM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal 1 . By co-opting KBTBD4, substrate receptor the CUL3–RING E3 ubiquitin ligase (CRL3) complex, promotes degradation LSD1–CoREST corepressor thereby limiting attrition 2,3 However, direct target and mechanism action remain unclear. Here we show that acts as molecular glue to induce high-affinity interactions between KBTBD4 HDAC1/2 promote degradation. Through proteomics chemical inhibitor studies, identify principal HDAC1/2. Cryo-electron microscopy analysis dimeric bound LSD1–HDAC1–CoREST complex identifies an asymmetric assembly in which single molecule enables pair KELCH-repeat propeller domains recruit HDAC1 catalytic domain. One partially masks rim active site, exploited by extend E3–neosubstrate interface. The other cooperatively strengthens binding through distinct overall CoREST–HDAC1/2–KBTBD4 interaction further buttressed endogenous cofactor inositol hexakisphosphate, second glue. functional relevance quaternary surfaces demonstrated base editor scanning delineating its action, reveal how cooperativity offered CRL3 can be leveraged small degrader.

Язык: Английский

Процитировано

4
Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry DOI Creative Commons

Tom Dixon,

Derek MacPherson, Barmak Mostofian

и другие.

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 6, 2022

Targeted protein degradation (TPD) is a promising approach in drug discovery for degrading proteins implicated diseases. A key step this process the formation of ternary complex where heterobifunctional molecule induces proximity an E3 ligase to interest (POI), thus facilitating ubiquitin transfer POI. In work, we characterize 3 steps TPD process. (1) We simulate SMARCA2 bromodomain and VHL by combining hydrogen-deuterium exchange mass spectrometry with weighted ensemble molecular dynamics (MD). (2) conformational heterogeneity using Hamiltonian replica simulations small-angle X-ray scattering. (3) assess ubiquitination POI context full Cullin-RING Ligase, confirming experimental ubiquitinomics results. Differences efficiency can be explained lysine residues on relative ubiquitin.

Язык: Английский

Процитировано

63
PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies DOI Creative Commons

Nuwayo Ishimwe Sincere,

Krishnan Anand, Sumel Ashique

и другие.

Molecules, Год журнала: 2023, Номер 28(10), С. 4014 - 4014

Опубликована: Май 10, 2023

A potential therapeutic strategy to treat conditions brought on by the aberrant production of a disease-causing protein is emerging for targeted breakdown using PROTACs technology. Few medications now in use are tiny, component-based and utilize occupancy-driven pharmacology (MOA), which inhibits function short period time temporarily alter it. By utilizing an event-driven MOA, proteolysis-targeting chimeras (PROTACs) technology introduces revolutionary tactic. Small-molecule-based heterobifunctional hijack ubiquitin–proteasome system trigger degradation target protein. The main challenge PROTAC’s development facing find potent, tissue- cell-specific PROTAC compounds with favorable drug-likeness standard safety measures. ways increase efficacy selectivity focus this review. In review, we have highlighted most important discoveries related proteins PROTACs, new approaches boost proteolysis’ effectiveness development, promising future directions medicine.

Язык: Английский

Процитировано

37