Biologics-based degraders - an expanding toolkit for targeted-protein degradation

Derek VanDyke; Jonathan D Taylor; Kyle J Kaeo; James Hunt; Jamie B Spangler

doi:10.1016/j.copbio.2022.102807

Biologics-based degraders - an expanding toolkit for targeted-protein degradation

Curr Opin Biotechnol. 2022 Dec:78:102807. doi: 10.1016/j.copbio.2022.102807. Epub 2022 Sep 27.

Authors

Derek VanDyke¹, Jonathan D Taylor², Kyle J Kaeo³, James Hunt², Jamie B Spangler⁴

Affiliations

¹ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA.
² Biologics Engineering, R&D, AstraZeneca, Cambridge, UK.
³ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].

Abstract

Targeted protein degradation (TPD) is a broadly useful proteome editing tool for biological research and therapeutic development. TPD offers several advantages over functional inhibition alone, including the ability to target previously undruggable proteins and the substantial and sustained knockout of protein activity. A variety of small molecule approaches hijack endogenous protein degradation machinery, but are limited to proteins with a cytosolic domain and suitable binding pocket. Recently, biologics-based methods have expanded the TPD toolbox by allowing access to extracellular and surface-exposed proteins and increasing target specificity. Here, we summarize recent advances in the use of biologics to deplete proteins through either the ubiquitin-proteasome system or the lysosomal degradation pathway, and discuss routes to their effective delivery as potential therapeutic interventions.

Publication types

Review

MeSH terms

Proteasome Endopeptidase Complex* / metabolism
Proteolysis
Proteome / metabolism
Ubiquitin* / metabolism

Substances

Proteasome Endopeptidase Complex
Ubiquitin
Proteome

Grants and funding

R01 EB029455/EB/NIBIB NIH HHS/United States