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Development of Oligomeric Mannose-6-phosphonate Conjugates for Targeted Protein Degradation

Christopher M Stevens1, Yaxian Zhou1, Peng Teng1

  • 1Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin - Madison Madison, Wisconsin 53705, United States.

ACS Medicinal Chemistry Letters
|June 14, 2023
PubMed

Insights

Lysosome targeting chimeras (LYTACs) are a novel protein degradation technique. Researchers developed mannose-6-phosphonate (M6Pn)-peptide conjugates for LYTACs, enabling targeted protein degradation via the mannose-6-phosphate receptor (M6PR).

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Lysosome targeting chimeras (LYTACs) represent an emerging strategy for targeted protein degradation.
  • LYTACs leverage cellular internalization pathways to deliver extracellular proteins to lysosomes for degradation.
  • The mannose-6-phosphate receptor (M6PR) is a key internalization receptor utilized in LYTAC technology.

Purpose of the Study:

  • To develop novel mannose-6-phosphonate (M6Pn)-peptide conjugates for LYTAC applications.
  • To enable targeted degradation of extracellular proteins using the M6PR pathway.
  • To facilitate the therapeutic development of M6Pn-based LYTACs.

Main Methods:

  • Synthesis of structurally defined M6Pn-peptide conjugates.
  • Conjugation of M6Pn-peptides to various targeting ligands.
  • Assessment of M6Pn-LYTACs for protein internalization and lysosomal degradation via M6PR.

Main Results:

  • Successful development of a series of well-defined M6Pn-peptide conjugates.
  • Demonstrated capability of M6Pn-LYTACs to internalize and degrade target extracellular proteins through M6PR.
  • Established the potential of M6Pn-based conjugates for broad therapeutic applications.

Conclusions:

  • M6Pn-peptide conjugates are effective tools for developing LYTACs.
  • This approach enables targeted degradation of extracellular proteins via M6PR.
  • The developed M6Pn-based LYTACs hold significant promise for therapeutic interventions.

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