Thyclotide Peptide Conjugates with Cell Permeability & Inhibitory Activity

Thyclotides are oligomeric molecules with chiral tetrahydrofuran (THF) diamine units consisting of either R,R or S,S stereochemistry. Thyclotide sequences with R,R stereochemistry bind to complementary DNA and RNA sequences with strong affinity and sequence specificity, while thyclotides with S,S stereochemistry have a helical handedness that does not allow binding to DNA or RNA. Thyclotides are cell permeable and can be used to suppress microRNA activity in cells. Peptides are oligomeric molecules consisting of amino acids found in proteins as well as other non-natural amino acids. Peptides are often developed as inhibitors of enzymes and protein-protein interactions, yet peptides typically are poor drugs as they do not penetrate cell membranes therefore have low bioactivity. NIDDK investigators have discovered that thyclotides can be covalently conjugated to peptides that are enzyme inhibitors to enhance the cell permeability of the peptide. Using thyclotide to enhance peptide cell penetration is a novel way to help peptides gain entry into cells to improve their bioavailability. Using thyclotides+peptide conjugates may greatly expand the range of therapeutic applications of peptide inhibitors.