Aptamer Proteolysis-Targeting Chimeras (PROTACs): A Novel Strategy to Combat Drug Resistance in Estrogen Receptor α-Positive Breast Cancer DOI Creative Commons

Ying Feng,

Zhilin Zhang, Haowei Zhang

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(12), P. 3945 - 3954

Published: Nov. 14, 2024

Breast cancer with positive expression of estrogen receptor α (ERα+) accounts for 70% breast cases, whose predominant treatment is currently endocrine therapy. The main strategy therapy ERα+ to inhibit the ERα signaling pathway and downregulate levels, which often results in mutations ligand-binding domain (LBD) ERα, leading significant resistance subsequent patients. To combat drug resistance, we first proposed a novel aptamer PROTAC through specifically targeted degradation via targeting DNA-binding (DBD) ERα. We proved that this capable ubiquitination, inhibition proliferation cells tamoxifen-resistant cells. Furthermore, investigated mechanisms involved overcoming resistance. By circumventing associated LBD our approach provides promising avenue discovery new therapeutic agents.

Language: Английский

Current developments of SELEX technologies and prospects in the aptamer selection with clinical applications DOI Creative Commons
Danny CHINCHILLA-CÁRDENAS, Juan Sebastian Cruz-Méndez, Julieth Michel Petano-Duque

et al.

Journal of Genetic Engineering and Biotechnology, Journal Year: 2024, Volume and Issue: 22(3), P. 100400 - 100400

Published: July 26, 2024

Aptamers are single-stranded oligonucleotide sequences capable of binding to specific ligands with high affinity. In this manner, they like antibodies but have advantages such as lower manufacturing costs, immunogenicity, fewer batch-to-batch differences, a longer shelf life, tolerance different molecular milieus, and greater number potential targets. Due their special features, been used in drug delivery, biosensor technology, therapy, diagnostics. The methodology that allowed its production was the "Systematic Evolution Ligands by Exponential enrichment" (SELEX). Unfortunately, traditional protocol is time-consuming laborious. Therefore, numerous variants considerable optimization steps developed, nonetheless, there still challenges achieving real applications clinical field. Among them, control vivo activities, fast renal filtration, degradation nucleases toxicity testing. This review focuses on current technologies based SELEX, critical factors for successful aptamer selection, upcoming biomedical biotechnological applications.

Language: Английский

Citations

9
Targeted degradation of membrane and extracellular proteins with LYTACs DOI

Yuyang Li,

Yang Yang, Renshuai Zhang

et al.

Acta Pharmacologica Sinica, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Language: Английский

Citations

9
Targeted Degradation of HCV Polymerase by GalNAc-Conjugated ApTACs for Pan-Genotypic Antiviral Therapy with High Resistance Barriers DOI
Wei Pan, Sijin Wu, Honglin Zhou

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Although interferon-free direct-acting antivirals have led to significant advancements in the treatment HCV infection, high genetic variability and emergence acquired drug resistance pose potential threats their effectiveness. In this study, we develop broad-spectrum aptamer-based proteolysis targeting chimera, designated dNS5B, which effectively degrades both pan-genotypic NS5B polymerase drug-resistant mutants through ubiquitin proteasome system. To achieve hepatocyte-specific uptake, further Gal-dNS5B by coupling dNS5B with trivalent N-acetylgalactosamine (tri-GalNAc), ligand for liver-specific asialoglycoprotein receptor. exclusively accumulates hepatocytes suppresses replication degrading NS5B. Collectively, our research lays groundwork scalable strategy development antiviral medications aimed at addressing current future challenges posed hepatitis viruses other re-emerging viral pandemics.

Language: Английский

Citations

0
Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation DOI Creative Commons
Zhihao Yang, Miao Chen,

Ruixin Ge

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 13, 2025

As a crucial element of proteolysis targeting chimeras (PROTACs), the choice E3 ubiquitin ligase significantly influences degradation efficacy and selectivity. However, available arsenal ligases for PROTAC development remains underexplored, severely limiting scope targeted protein degradation. In this study, we identify non-inhibitory aptamer ZYG11B, substrate receptor Cullin 2-RING complex, as an warhead This aptamer-based platform, termed ZATAC, is facilely produced through bioorthogonal chemistry or self-assembly shows promise in eliminating several undruggable target proteins, including nucleolin (NCL), SRY-box transcription factor 2 (SOX2), mutant p53-R175H, underscoring its universality versatility. To specifically deliver ZATACs into cancer cells, further develop DNA three-way junction-based (3WJ-ZATACs) by integrating additional that selectively recognizes overexpressed on surface cells. The 3WJ-ZATACs demonstrate vivo tumor-specific distribution achieve dual-target degradation, thereby suppressing tumor growth without causing noticeable toxicity. summary, represent general, modular, straightforward platform offering insights potential other untapped ligases. Enhancing important PROTACs development. Here, authors aptameric ligand to CRL2ZYG11B ligase, providing

Language: Английский

Citations

0
Histone deacetylase 6 inhibition attenuates pathological cardiac hypertrophy by promoting autophagy through MAP1LC3B ubiquitination DOI
Jiayu Yao, Xiaoou Sun, YOU-SHENG CHEN

et al.

The Journal of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: April 11, 2025

Abstract Cardiac hypertrophy is an adaptive response of the heart to pathological stimuli that may lead cardiac dysfunction and failure. Histone deacetylase 6 (HDAC6) participates in progression multiple cardiovascular diseases, including chronic hypertension, ischemic stroke, acute injury. A delicate balance autophagy regulates homeostasis, whereas dysregulated involved myocardial hypertrophy. However, whether HDAC6 by regulating remains unclear. In this paper, we report for first time isoproterenol (ISO)‐induced interacting with ubiquitinating MAP1LC3B. First, expression level was found be increased models induced ISO. overexpression promoted hypertrophic genes enhanced cell surface area. Conversely, inhibition attenuated ISO‐induced responses. Mechanistically, responses negatively autophagy. Furthermore, interacted MAP1LC3B mediated its monoubiquitination, thereby contributing reduced levels impaired Inhibition activity mice abrogated effects ISO restoring expression. summary, our data demonstrate limiting availability suppressing © 2025 The Pathological Society Great Britain Ireland.

Language: Английский

Citations

0
Strategies for p53 Activation and Targeted Inhibitors of the p53-Mdm2/MdmX Interaction DOI Creative Commons

Ye Huang,

Li Wang,

Yuke Zhou

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(8), P. 583 - 583

Published: April 12, 2025

p53 is a tumor suppressor gene and regarded as one of the most crucial genes in protecting humans against cancer. The protein Mdm2 its homolog MdmX serve negative regulators p53. In nearly half cancer cells, there an overexpression MdmX, which inhibit activity. Furthermore, Mdm2’s E3 ubiquitin ligase activity promotes ubiquitination degradation Therefore, blocking interaction between Mdm2/MdmX to prevent wild-type effective strategy for inhibiting growth. This paper primarily discusses regulatory relationship p53, Mdm2, provides review current status p53-Mdm2/MdmX inhibitors. It aims offer theoretical foundation research direction future discovery design targeted inhibitors interaction.

Language: Английский

Citations

0
The Peptide PROTAC Modality: A New Strategy for Drug Discovery DOI Creative Commons
Youmin Zhu, Yu Dai,

Yun-Cai Tian

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(4)

Published: March 24, 2025

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC provides new ideas for treating various diseases by inducing degradation target proteins. Especially peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review detailed description key components, mechanisms, design principles elaborates applications skin‐related diseases, oncology, other potential therapeutic fields, analyzes advantages challenges, looks forward future development prospects. The not only opens up paths development, but also solving resistance safety issues faced traditional small‐molecule drugs. Compared with PROTACs such as multitargeting, biodegradability, low toxicity, flexibility design. With deepening continuous maturity technology, are expected one important strategies discovery, providing hope treatment more intractable diseases. Peptide ushering era precision medicine.

Language: Английский

Citations

0
Targeting neurodegenerative disease-associated protein aggregation with proximity-inducing modalities DOI

Ruixin Ge,

Miao Chen, Qingchao Li

et al.

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Language: Английский

Citations

0
Hydrophobic CPP/HDO Conjugates: A New Frontier in Oligonucleotide-Warheaded PROTAC Delivery DOI
Miyako Naganuma, Nobumichi Ohoka,

Motoharu Hirano

et al.

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

Published: Jan. 1, 2024

Proteolysis-targeting chimeras (PROTACs) have emerged as a potent strategy for inducing targeted degradation of proteins, offering promising therapeutic potential to treat diseases such cancer. However, oligonucleotide-based PROTACs face significant delivery challenges because their anionic nature and chemical instability. To address these issues, we developed novel hydrophobic cell-penetrating peptide (CPP) heteroduplex oligonucleotide (HDO)-conjugated PROTAC,

Language: Английский

Citations

3
CYLD/HDAC6 signaling regulates the interplay between epithelial-mesenchymal transition and ciliary homeostasis during pulmonary fibrosis DOI Creative Commons
Hua Ni, Miao Chen, Dan Dong

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(8)

Published: Aug. 9, 2024

The primary cilium behaves as a platform for sensing and integrating extracellular cues to control plethora of cellular activities. However, the functional interaction this sensory organelle with epithelial-mesenchymal transition (EMT) during pulmonary fibrosis remains unclear. Here, we reveal critical role cylindromatosis (CYLD) in reciprocally linking EMT program ciliary homeostasis fibrosis. A close correlation between cilia is observed bleomycin-induced well TGF-β-induced model. Mechanistic study reveals that downregulation CYLD underlies crosstalk by inactivating histone deacetylase 6 (HDAC6) Moreover, manipulation an effective means modulate program. Collectively, these results identify pivotal CYLD/HDAC6 signaling regulating reciprocal interplay

Language: Английский

Citations

1