Synthetic 1-deoxynojirimycin N-substituted peptides offer prolonged disruption to N-linked glycan processing

Area of Science:

• Biochemistry
• Glycobiology
• Medicinal Chemistry

Background:

• N-linked glycosylation is crucial for protein folding and function.
• Inhibitors of α-glucosidases can modulate N-linked glycan processing.
• Targeting drugs to specific cellular compartments like the ER can enhance efficacy.

Purpose of the Study:

• To synthesize and evaluate 1-deoxynojirimycin (DNJ) N-linked peptides as ER-targeted inhibitors.
• To compare the efficacy of DNJ N-linked peptides with free iminosugars in cell-based assays.
• To assess the potential of ER-retention sequences for prolonging drug activity.

Main Methods:

• Synthesis of DNJ N-linked peptides.
• In vitro IC50 determination against α-glucosidases I and II.
• Cell-based assays measuring N-linked glycan processing disruption.
• Low inhibitor washout studies to assess inhibitor stability and retention.

Main Results:

• DNJ N-linked peptides showed micromolar IC50 values against α-glucosidases I and II.
• DNJ-KDEL demonstrated superior performance over free iminosugar 3 in extended cell-based studies (3 days).
• DNJ-KDEL retained 13% activity after washout, while NB-DNJ inhibition decreased to zero.

Conclusions:

• ER-targeting of iminosugars via N-linked peptides can prolong their inhibitory activity.
• The DNJ-KDEL conjugate represents a promising strategy for ER-specific drug delivery.
• This modular approach allows for the incorporation of novel, more potent iminosugars in the future.