Retro-Inverso Prosaptide Peptides Retain Bioactivity, Are Stable In Vivo, and Are Blood-Brain Barrier Permeable

Prosaptide (trademark of Myelos Corporation, San Diego, CA) peptides are based on the 14-amino-acid neurotrophic sequence of human prosaposin and, like the parent protein, have potent neurotrophic and neuroprotective properties. We previously examined the in vivo stability of a series of bioactive Prosaptide peptides and designed peptides with increased enzymatic stability in the central and peripheral nervous systems. In this article, we examined the stability, biological activity, and permeability of the blood-brain barrier to retro-inverso Prosaptide peptidomimetics. Retro-inversion both reverses the primary sequence and replaces L-amino acids with D-amino acids. We examined the bioactivity of five peptidomimetics, Prosaptides D1-D5. Prosaptide D1, a peptide containing all D-amino acids with the primary sequence intact, was inactive. However, four retro-inverso peptidomimetics, Prosaptides D2-D5 retained bioactivity in neurite outgrowth and [(35)S]GTPgammaS binding assays. We focused on Prosaptide D4 as a prototypical retro-inverso Prosaptide peptidomimetic for further study. (125)I-Prosaptide D4 remained intact in brain or serum for 60 min after i.v. administration and was transported across the blood-brain barrier with a unidirectional influx constant of 2.5 x 10(-4) ml. g(-1). min(-1). We conclude that retro-inverso Prosaptide peptidomimetics are excellent candidates for development as therapeutics for central nervous system neurodegeneration.