Targeting GLUT1 degradation with assembling glycopeptide for cancer inhibition

Abstract

The upregulation of GLUT1 expression is closely associated with poor patient survival rates, highlighting its significance as a therapeutic target in tumor therapy. While efforts have predominantly focus on developing GLUT1 inhibitors, the crucial role of GLUT1 has been largely overlooked. Herein, we introduce a straightforward strategy involving the integration of mannose moiety into self-assembling peptides to exploit GLUT1 for enhanced cellular internalization. Additionally, the accumulation of glycosylated peptides prompts the self-assembly into nanofibers within lysosomes, initiating GLUT1 degradation and inducing lysosomal dysfunction, ultimately leading to cell death. Notably, peptides lacking mannose exhibit minimal cytosolic internalization, resulting in insignificant effects on GLUT1 expression and cellular functionality. Furthermore, in vivo studies demonstrated this assembling glycopeptide shows comparable efficacy to the chemotherapeutic drug Taxol. By simple incorporating mannose into self-assembling peptides and leveraging GLUT1′s role in modulating the cellular uptake of amphiphile peptides, this facile approach not only offers valuable insights for designing cell-permeable therapeutic peptide drugs, also holds promise for targeting the degradation of disease-associated proteins.