The identification of leptin-derived peptides that are taken up by the brain

We studied the brain uptake of leptin and of a set of peptides whose combined sequences spanned the entire mature human leptin protein. We compared their uptake to that of albumin and IgG. Two of these peptides, consisting of residues 1–33 and 61–90, demonstrated brain uptake on a par with leptin protein itself, and significantly higher than the uptake of albumin and IgG. Further investigation revealed a peptide, 12–32, with higher uptake than its parent peptide 1–33. Peptide 61–90 had the highest brain uptake, and this was shown to be saturable. Comparison of these brain-permeant peptides with the published structure of the leptin:leptin receptor complex revealed a high degree of correlation. All of the leptin residues that have been identified as important receptor-binding contacts appeared to have a role in brain uptake, indicating that receptor binding is an intrinsic part of transport across the blood–brain barrier. The effect of these peptides as leptin agonists or antagonists remains to be investigated. The newly identified peptides also have a potentially large role as carrier molecules for new brain therapeutics, since peptides can be readily coupled to other molecules.