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VAAAIALPAIVP-Cys is a hydrophobic, amphipathic 12-residue peptide with a C-terminal cysteine for conjugation. It is derived from sequences optimized for intracellular delivery, acting as a cell-penetrating peptide (CPP) to facilitate transport of biologics, proteins, or small molecules across the plasma membrane. Such peptides are particularly useful in therapeutic delivery systems where target engagement requires cytosolic or nuclear localization (US10975132B2).
Molecular details
Sequence: V-A-A-A-I-A-L-P-A-I-V-P-C. The peptide is highly hydrophobic, with alternating aliphatic residues promoting membrane interaction. The terminal cysteine allows for site-specific conjugation via thiol-reactive chemistries such as maleimide coupling. Its small size enhances diffusion and cellular uptake efficiency, while maintaining structural flexibility.
Functional roles & mechanism
VAAAIALPAIVP-Cys functions as a CPP, enabling intracellular transport of linked cargo molecules. Its hydrophobicity facilitates direct interaction with lipid bilayers, promoting endocytosis-independent membrane translocation or enhancing endosomal escape. In the patent, this peptide was fused to SOCS3 protein constructs to improve intracellular delivery and modulate JAK/STAT signaling pathways, demonstrating that the CPP can carry functional proteins into the cytosol and nucleus.
Applications
• Therapeutic delivery: Intracellular delivery of protein therapeutics, such as SOCS3 or other signaling modulators.
• Drug conjugates: Facilitates conjugation and cytosolic delivery of small molecules, peptides, or nucleic acids.
• Research tools: Cellular uptake studies, intracellular signaling modulation, and protein localization experiments.
• Biomaterials functionalization: Can be immobilized on nanoparticles or scaffolds to enhance cellular internalization.
Peer-reviewed context
While VAAAIALPAIVP-Cys is described in US10975132B2, its function as a hydrophobic cell-penetrating peptide is consistent with literature on amphipathic CPPs such as penetratin or transportan, which facilitate intracellular delivery of biologics (Madani et al., Int J Mol Sci, 2011; Bechara & Sagan, FEBS Lett, 2013). Its hydrophobic residues mimic lipid-interacting CPP domains, enabling efficient translocation into mammalian cells.
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