Bifunctional small molecules that mediate the degradation of extracellular proteins

Caianiello, David; Zhang, Mengwen; Ray, Jason D.; Howell, Rebecca; Swartzel, Jake C; Branham, Emily; Chirkin, Egor; Sabbasani, Venkata R.; Gong, Angela; McDonald, D; Muthusamy, Viswanathan; Spiegel, David A.

doi:10.1038/s41589-021-00851-1

Cited by 115 publications

(105 citation statements)

References 49 publications

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“…ASGPR, a liver-specific lectin, found to be a major target of B and T cell autoantigenic in patients with liver diseases, has attracted long-term attention [ 27 ]. ASGPR-mediated drug delivery [ 15 , 28 ] and target protein degradation [ 29 , 30 ] suggest that changes in glycan modification on the surface of nanoparticles could affect its interaction with recipient cells. It has been reported that neuraminidase treatment increased the EV uptake by certain cells [ 11 ] and affected EV distribution in mice [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma

Yang

Guan

Pang

et al. 2022

Cells

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Hepatocellular carcinoma (HCC) is one of the dominating causes of cancer-related death throughout the world. Treatment options for patients with HCC vary, however, the lack of effective targeted drugs is the major reason for death in advanced HCC patients. In this study, a delivery system based on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) loaded with doxorubicin (Dox) was developed. In this system, we initially erased terminal linked α2–3 and α2–6 sialic acids on the surface of EVs by neuraminidase. The exhibition of galactose (Gal) and N-acetylgalactosamine (GalNAc) residues in treated MSC-EVs can specifically be recognized by asialoglycoprotein receptor (ASGPR) of hepatoma cells. Compared to free Dox and Dox-loaded EVs, desialylated EVs loaded with Dox significantly presented the improved cellular uptake, prioritized targeting efficacy, and had a better inhibiting effect in vitro and in vivo. Overall, the results of the present study of the demonstrated delivery system using desialylated MSC-EVs suggest its therapeutic potential for HCC.

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Section: Discussionmentioning

confidence: 99%

Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma

Yang

Guan

Pang

et al. 2022

Cells

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“… Name Target Target type Applied macromolecules Degradation pathway Ref. Bispecific aptamer chimeras PTK-7/Met Membrane protein Nucleic acid (aptamer) Lysosome 156 F-box/intrabody-targeted protein degradation RHOB-GTP Intracellular protein Antibody (nonobody) Proteasome 157 M6Pn-LYTACs ApoE4/EGFR/CD71/PD-L1 Extracellular/membrane protein Glycopeptide/antibody Lysosome 158 GalNAc-LYTACs EGFR/integrins/α-DNP antibody/MIF/NeutrAvidin Extracellular/membrane protein Tri-GalNAc/peptide/antibody Lysosome 159 , 160 , 161 Sweeping antibodies IL-6R/C5 Free antigen Antibody Lysosome 162 , 163 Abdegs or Seldegs IgG/trastuzumab Antibody Antigen Lysosome 164 , 165 …”

Section: Other Non-small Molecule Protein Degradersmentioning

confidence: 99%

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

Tong

et al. 2022

Acta Pharmaceutica Sinica B

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“…In addition, they prepared some degraders with different molecular weights, and demonstrated that the small degrader-antibody complexes were facilitated to internalization relative to the big complexes. Different from the aforementioned two studies, Spiegel’s group ( Caianiello et al, 2021 ) designed a class of bifunctional small molecules termed MoDE-A, which was composed of trivalent GalNAc, a PEG linker and a small-molecule ligand for binding the POI. This chimera was relatively small size and easily synthesized compared with LYTACs.…”

Section: Hijacking Non-ups Pathway For Protein Degradationmentioning

confidence: 99%

Major Advances in Emerging Degrader Technologies

Luo

et al. 2022

Front. Cell Dev. Biol.

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Recently, degrader technologies have attracted increasing interest in the academic field and the pharmaceuticals industry. As one of the degrader technologies, proteolysis-targeting chimeras (PROTACs) have emerged as an attractive pharmaceutical development approach due to their catalytic ability to degrade numerous undruggable disease-causing proteins. Despite the remarkable progress, many aspects of traditional PROTACs still remain elusive. Its expansion could lead to PROTACs with new paradigm. Currently, many reviews focused on the design and optimization strategies through summarizing classical PROTACs, application in diseases and prospect of PROTACs. In this review, we categorize various emerging PROTACs ranging from simply modified classical PROTACs to atypical PROTACs such as nucleic acid-based PROTACs, and we put more emphasis on molecular design of PROTACs with different strategies. Furthermore, we summarize alternatives of PROTACs as lysosome-targeting chimeras (LYTACs) and macroautophagy degradation targeting chimeras (MADTACs) based on different degradation mechanism despite of lysosomal pathway. Beyond these protein degraders, targeting RNA degradation with the potential for cancer and virus therapeutics has been discussed. In doing so, we provide our perspective on the potential development or concerns of each degrader technology. Overall, we hope this review will offer a better mechanistic understanding of emerging degraders and prove as useful guide for the development of the coming degrader technologies.

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Bifunctional small molecules that mediate the degradation of extracellular proteins

Cited by 115 publications

References 49 publications

Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma

Desialylated Mesenchymal Stem Cells-Derived Extracellular Vesicles Loaded with Doxorubicin for Targeted Inhibition of Hepatocellular Carcinoma

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

Major Advances in Emerging Degrader Technologies

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