Radical chemistry platform for lysosomal peptide-small molecule conjugates

Overview

This research proposes a new chemistry platform that uses radical Minisci reactions to combine validated cell-penetrating and blood-brain barrier (BBB)-penetrating peptides with small-molecule lysosomal agents. By leveraging an internal or N-terminal cysteine residue in short peptides, the platform generates alanyl radicals that react with arenes and heteroarenes, producing conjugates that unite the attributes of both components. The approach addresses a critical gap: the absence of a general method for merging known peptide carriers with small-molecule drug entities. Potential applications include new therapeutics for lysosomal disorders, expanded structure-activity relationship (SAR) data, and novel PET imaging ligands.

Technical specifications

Core chemistry approach:

• Radical Minisci functionalization of arenes and heteroarenes using peptide-derived radicals
• Phosphine-promoted radical desulfurization of cysteine residues to generate alanyl radicals
• Chemoselective formation of native N-terminal alanine or alanine-type linkages between peptides and small molecules
• Compatibility with heterocyclic small molecules known to modulate lysosomal function

Peptide carriers targeted for conjugation:

• Transportan 10
• Penetratin
• Pep H3
• Each equipped with N-terminal N-Acetyl cysteine residues

Small-molecule lysosomal agents targeted for conjugation:

• YM-201636
• SF-51
• Apilimod
• Chloroquine
• MI-SI

Planned validation activities:

• Screening of radical initiators and hydrogen-atom sources
• Determination of regioisomeric linkages on the arene component
• Characterization by NMR and high-resolution mass spectrometry (HRMS)
• Subsequent biological evaluation through partnership collaboration

Technology readiness level

This technology is at an early discovery stage. The proposed work involves approximately one year of synthetic chemistry and characterization to produce and validate new peptide-small molecule conjugates. Once the conjugates are synthesized and characterized, a downstream partnership will be required to evaluate the biological output, including activity in lysosomal disease models and BBB penetration. The platform is not yet validated in biological systems, and further development is needed before therapeutic or imaging applications can be pursued.