Identification of host factors for livestock and poultry viruses: genome-wide screening technology based on the CRISPR system DOI Creative Commons
Shijie Hu, Mailin Gan, Zhiyi Wei

et al.

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 21, 2024

Genome-wide CRISPR library screening technology is a gene function research tool developed based on the CRISPR/Cas9 gene-editing system. The clustered regularly interspaced short palindromic repeats/CRISPR-associated genes (CRISPR/Cas) system, considered third generation of editing after zinc finger nucleases (ZFN) and transcription activator-like effector (TALEN), widely used for various viral host factors. libraries are classified into three main categories different functions Cas9 enzymes: knockout (CRISPR KO) screening, transcriptional activation (CRISPRa) interference (CRISPRi) screening. Recently, genome-wide has been to identify factors that interact with viruses at stages, including adsorption, endocytosis, replication. By specifically modulating expression these factors, it becomes possible cultivate disease-resistant varieties, establish disease models, design develop vaccines, among other applications. This review provides an overview development technical processes as well its applications in identifying livestock poultry.

Language: Английский

Exploring Arylidene–Indolinone Ligands of Autophagy Proteins LC3B and GABARAP DOI
Alexandria N. Leveille,

Thomas Schwarzrock,

Hawley Brown

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(2), P. 271 - 277

Published: Jan. 6, 2025

We report the first structure–activity studies of arylidene–indolinone compound GW5074, which was reported as a ligand autophagy-related protein LC3B. The literature has conflicting information on binding affinity this compound, and there is some debate regarding its use component autophagy-dependent degrader compounds. developed an AlphaScreen assay to measure competitive inhibition known peptide ligands LC3B paralog GABARAP. Eighteen analogs were synthesized tested against both proteins. Inhibitory potencies found be in mid- high-micromolar range. 2D-NMR data revealed site GABARAP hydrophobic pocket 1, where native bind with aromatic side chain. Our results suggest that GW5074 binds micromolar affinity. These affinities could support further exploration targeted degradation, but only if off-target effects poor solubility can appropriately addressed.

Language: Английский

Citations

0
Implications of frequent hitter E3 ligases in targeted protein degradation screens DOI
Xiaoyu Zhang, Gabriel M. Simon, Benjamin F. Cravatt

et al.

Nature Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Language: Английский

Citations

0
Recommended Tool Compounds: Thienotriazolodiazepines-Derivatized Chemical Probes to Target BET Bromodomains DOI Creative Commons
Chuhui Huang, Claire L. Harris, Ghizal Siddiqui

et al.

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(4), P. 978 - 1012

Published: March 14, 2025

Thienotriazolodiazepines, including (+)-JQ1 (4), are well-known inhibitors of the bromodomain (BD) and extra-terminal domain (BET) family proteins. Despite suboptimal physicochemical properties as a drug candidate, such poor solubility half-life, (4) has proven an effective chemical probe with high target potency selectivity. (+)-JQ1-derived probes have played vital role in biology discovery over past decade, which is demonstrated by number impactful research studies published since disclosure 2010. In this review, we discuss development (+)-JQ1-derivatized decade their significant contribution to scientific research. Specifically, will summarize innovative label-free labeled probes, bivalent, covalent, photoaffinity well protein degraders, focus on design these probes.

Language: Английский

Citations

0
R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation DOI Creative Commons
Chao Zhong, Xiaoge Gao, Qi Chen

et al.

Autophagy, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

The presence of neuronal Lewy bodies mainly composed SNCA/α-synuclein aggregations is a pathological feature Parkinson disease (PD), whereas reducing SNCA protein levels may slow the progression this disease. We hypothesized that compounds enhancing SNCA's interaction with MAP1LC3/LC3 May increase its macroautophagic/autophagic degradation. Here, we conducted small molecule microarray (SMM)-based screening to identify such and revealed compound R406 could decrease in an autophagy-dependent manner. further validated proposed mechanism, which knockdown essential gene ATG5 for autophagy formation using inhibitor chloroquine (CQ) blocked effect R406. Additionally, also reduced phosphorylated serine 129 (p-S129-SNCA) preformed fibrils (PFFs)-induced cellular models rescued neuron degeneration.

Language: Английский

Citations

0
Covalent Proximity Inducers DOI Creative Commons
Nir London

Chemical Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

Molecules that are able to induce proximity between two proteins finding ever increasing applications in chemical biology and drug discovery. The ability introduce an electrophile make such inducers covalent can offer improved properties as selectivity, potency, duration of action, reduced molecular size. This concept has been heavily explored the context targeted degradation particular for bivalent molecules, but recently, additional reported other contexts, well monovalent glues. is a comprehensive review inducers, aiming identify common trends current gaps their discovery application.

Language: Английский

Citations

2
Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP DOI Creative Commons
Alexandria N. Leveille,

Thomas Schwarzrock,

Hawley Brown

et al.

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

Published: Feb. 25, 2024

We report the first structure-activity studies of arylidene-indolinone compound

Language: Английский

Citations

1
Design, Synthesis, and Activity Evaluation of BRD4 PROTAC Based on Alkenyl Oxindole-DCAF11 Pair DOI
Man Zhao, Wenjing Ma,

Jimmy T. Liang

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19428 - 19447

Published: Oct. 30, 2024

Proteolytic targeting chimera (PROTAC) represent an advanced strategy for undruggable proteins, and the molecular warheads E3 ligases play a crucial role. Recently, we explored alkenyl oxindole warhead ligase DCAF11 sought to validate its potential. In this study, synthesized range of BRD4 PROTACs (8a–8o, 14a–14f, 22a–22m) with modified developed high-throughput screening system based on high-content imaging. We identified L134 (22a) as potent degrader, achieving degradation (Dmax > 98%, DC50 = 7.36 nM) demonstrating antitumor activity. Mechanically, by was mediated through ubiquitin-proteasome in DCAF11-dependent manner. Therefore, study provides rapid method effective highlights PROTAC oxindole-DCAF11 pair promising candidate treating BRD4-driven cancers.

Language: Английский

Citations

0
Identification of host factors for livestock and poultry viruses: genome-wide screening technology based on the CRISPR system DOI Creative Commons
Shijie Hu, Mailin Gan, Zhiyi Wei

et al.

Frontiers in Microbiology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 21, 2024

Genome-wide CRISPR library screening technology is a gene function research tool developed based on the CRISPR/Cas9 gene-editing system. The clustered regularly interspaced short palindromic repeats/CRISPR-associated genes (CRISPR/Cas) system, considered third generation of editing after zinc finger nucleases (ZFN) and transcription activator-like effector (TALEN), widely used for various viral host factors. libraries are classified into three main categories different functions Cas9 enzymes: knockout (CRISPR KO) screening, transcriptional activation (CRISPRa) interference (CRISPRi) screening. Recently, genome-wide has been to identify factors that interact with viruses at stages, including adsorption, endocytosis, replication. By specifically modulating expression these factors, it becomes possible cultivate disease-resistant varieties, establish disease models, design develop vaccines, among other applications. This review provides an overview development technical processes as well its applications in identifying livestock poultry.

Language: Английский

Citations

0