Advances in targeted degradation of endogenous proteins

Sascha Roth, Luke Fulcher, Gopal Sapkota (Lead / Corresponding author)

Research output: Contribution to journalReview article

1 Citation (Scopus)
164 Downloads (Pure)

Abstract

Protein silencing is often employed as a means to aid investigations in protein function and is increasingly desired as a therapeutic approach. Several types of protein silencing methodologies have been developed, including targeting the encoding genes, transcripts, the process of translation or the protein directly. Despite these advances, most silencing systems suffer from limitations. Silencing protein expression through genetic ablation, for example by CRISPR/Cas9 genome editing, is irreversible, time consuming and not always feasible. Similarly, RNA interference approaches warrant prolonged treatments, can lead to incomplete protein depletion and are often associated with off-target effects. Targeted proteolysis has the potential to overcome some of these limitations. The field of targeted proteolysis has witnessed the emergence of many methodologies aimed at targeting specific proteins for degradation in a spatio-temporal manner. In this review, we provide an appraisal of the different targeted proteolytic systems and discuss their applications in understanding protein function, as well as their potential in therapeutics.

Original languageEnglish
Pages (from-to)2761-2777
Number of pages17
JournalCellular and Molecular Life Sciences
Volume76
Issue number14
Early online date27 Apr 2019
DOIs
Publication statusE-pub ahead of print - 27 Apr 2019

Fingerprint

Proteolysis
Proteins
Clustered Regularly Interspaced Short Palindromic Repeats
Gene Targeting
Protein Biosynthesis
RNA Interference
Therapeutics

Keywords

  • Affinity-directed protein missile
  • AiD
  • Auxin
  • CRBN
  • FKBP12
  • HALO
  • Monobody
  • Nanobody
  • PROTAC
  • Proteasome
  • Proteolysis targeting chimera
  • Thalidomide
  • Ubiquitin
  • VHL

Cite this

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title = "Advances in targeted degradation of endogenous proteins",
abstract = "Protein silencing is often employed as a means to aid investigations in protein function and is increasingly desired as a therapeutic approach. Several types of protein silencing methodologies have been developed, including targeting the encoding genes, transcripts, the process of translation or the protein directly. Despite these advances, most silencing systems suffer from limitations. Silencing protein expression through genetic ablation, for example by CRISPR/Cas9 genome editing, is irreversible, time consuming and not always feasible. Similarly, RNA interference approaches warrant prolonged treatments, can lead to incomplete protein depletion and are often associated with off-target effects. Targeted proteolysis has the potential to overcome some of these limitations. The field of targeted proteolysis has witnessed the emergence of many methodologies aimed at targeting specific proteins for degradation in a spatio-temporal manner. In this review, we provide an appraisal of the different targeted proteolytic systems and discuss their applications in understanding protein function, as well as their potential in therapeutics.",
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author = "Sascha Roth and Luke Fulcher and Gopal Sapkota",
note = "SR is supported by GlaxoSmithKline through the Division of Signal Transduction Therapy collaboration. LJF is supported by the U.K. MRC PhD studentship and the Queens College Scholarship, University of Dundee. GPS is supported by the U.K. MRC (Grant MC_UU_12016/3) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy (Boehringer-Ingelheim, GlaxoSmithKline, Merck-Serono). The authors declare no conflicts of interests. The authors would like to apologise for any relevant study that may have been missed inadvertently in this review.",
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Advances in targeted degradation of endogenous proteins. / Roth, Sascha; Fulcher, Luke; Sapkota, Gopal (Lead / Corresponding author).

In: Cellular and Molecular Life Sciences, Vol. 76, No. 14, 27.04.2019, p. 2761-2777.

Research output: Contribution to journalReview article

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AU - Fulcher, Luke

AU - Sapkota, Gopal

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N2 - Protein silencing is often employed as a means to aid investigations in protein function and is increasingly desired as a therapeutic approach. Several types of protein silencing methodologies have been developed, including targeting the encoding genes, transcripts, the process of translation or the protein directly. Despite these advances, most silencing systems suffer from limitations. Silencing protein expression through genetic ablation, for example by CRISPR/Cas9 genome editing, is irreversible, time consuming and not always feasible. Similarly, RNA interference approaches warrant prolonged treatments, can lead to incomplete protein depletion and are often associated with off-target effects. Targeted proteolysis has the potential to overcome some of these limitations. The field of targeted proteolysis has witnessed the emergence of many methodologies aimed at targeting specific proteins for degradation in a spatio-temporal manner. In this review, we provide an appraisal of the different targeted proteolytic systems and discuss their applications in understanding protein function, as well as their potential in therapeutics.

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