Designing stable blood-brain barrier-permeable prosaptide peptides for treatment of central nervous system neurodegeneration.
Prosaposin-derived peptides have been proposed as potential therapeutics for neurodegenerative diseases. Previously, we reported that the minimal length for bioactivity was 12 amino acids, and key amino acids were described based on interspecies conservation. In this article, we have further investigated the sequence requirements for bioactive Prosaptide (Myelos Corporation) peptides in terms of length and amino acid identity. The use of Prosaptide peptides for treatment of central nervous system (CNS) disorders requires that they are stable in vivo. Although robust effects of our prototypical peptide Prosaptide TX14(A) have been shown in the peripheral nervous system, minimal success has been achieved when treating the CNS in rats and this may be due to instability of Prosaptide TX14(A) in brain. Herein, we demonstrate that, indeed, Prosaptide TX14(A) is rapidly degraded in the brain and we have attempted to design prosaptides with increased CNS stability. One peptide, Prosaptide TX15-2, shows increased stability in brain and may be of use in the treatment of CNS disorders. With the aim of designing Prosaptide peptides that may be systemically administered for CNS treatment, we have investigated the blood-brain barrier permeability of Prosaptide TX14(A) and TX15-2. Both of these peptides cross the blood-brain barrier via a nonspecific mechanism.
Taylor
E M
EM
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0634, USA.
Otero
D A
DA
Banks
W A
WA
O'Brien
J S
JS
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D015195:Drug Design; D006023:Glycoproteins / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy*; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011498:Protein Precursors / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049231:Saposins; D013329:Structure-Activity Relationship
D006023:Glycoproteins; D018696:Neuroprotective Agents; D011498:Protein Precursors; C483347:Psap protein, rat; D049231:Saposins; D016244:Guanosine 5'-O-(3-Thiotriphosphate)