Protective Peptides That Are Orally Active and Mechanistically Nonchiral

Abstract

Previous reports identified two peptides that mimic the action of neuroprotective proteins derived from astrocytes. These peptides, NAPVSIPQ and SALLRSIPA, prevent neuronal cell death produced by electrical blockade, N-methyl-D-aspartate, and ␤-amyloid peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). In the present study, all Damino acid peptides of NAPVSIPQ and SALLRSIPA were synthesized and compared respectively to the corresponding all L-amino acid peptides. In rat cerebral cortical test cultures cotreated with 1 M tetrodotoxin, the D-amino acid peptides produced similar potency and efficacy for neuroprotection as that observed for their respective L-amino acid peptides. Since all these peptides tested individually exhibited attenuation of efficacy at concentrations of Ͼ10 pM, combinations of these peptides were tested for possible synergies. Equimolar D-NAPVSIPQ and D-SALLRSIPA combination treatment produced potent neuroprotection (EC 50 , 0.03 fM) that did not attenuate with increasing concentrations. Similarly, the combination of L-NAPVSIPQ and D-SALLRSIPA also had high potency (EC 50 , 0.07 fM) without attenuation of efficacy. Combined administration of peptides was tested in a model of fetal alcohol syndrome and in a model of learning impairment: apolipoprotein E knockout mice. Intraperitoneal administration of D-NAPV-SIPQ plus D-SALLRSIPA to pregnant mice (embryonic day 8) attenuated fetal demise after treatment with an acute high dose of alcohol. Furthermore, oral administration of D-NAPVSIPQ plus D-SALLRSIPA significantly increased fetal survival after maternal alcohol treatment. Apolipoprotein E knockout mice injected with D-NAPVSIPQ plus D-SALLRSIPA showed improved performance in the Morris water maze. These studies suggest therapeutic potential for the combined administration of neuroprotective peptides that can act through a mechanism independent of chiral recognition.

Peptide-Mediated Protection from Ethanol-Induced Neural Tube Defects

“…This observation is consistent with recent studies showing a lack of stereospecifi city for NAP antagonism of ethanol inhibition of L1 adhesion and NAP protection against ethanolinduced fetal growth retardation and fetal demise [Wilkemeyer et al, 2004;Brenneman et al, 2004]. D -Peptides are frequently more stable than L -peptides in vivo , because they are more resistant to peptidases.…”

Novel neuroprotective neurotrophic NAP analogs targeting metal toxicity and oxidative stress: potential candidates for the control of neurodegenerative diseases

“…NAP was reported to possess potent neuroprotective action in cell cultures and animal models (Gozes et al, 2003). Various NAP analogs were synthesized and investigated, some of which have been shown to possess, in vitro and=or in vivo, neuroprotective activities comparable to their parent peptide NAP (Wilkemeyer et al, 2003;Brenneman et al, 2004). However, NAP and all its known analogs appear to have poor affinity for metal ions (Fe 3þ , Cu 2þ , Zn 2þ ).…”

PolyADP-Ribosylation Is Involved in Neurotrophic Activity

“…These two structurally related peptides were derived by peptide activity scanning from two glial proteins, ADNF Brenneman et al, 1998) and activity-dependent neuroprotective protein (Bassan et al, 1999). Whereas NGF, BDNF, and NT-3 act via phosphorylation of Trk receptor tyrosine kinases, NAP and ADNF-9 may not need surface receptors and rather act like poreforming peptides (Brenneman et al, 2004;Chiba et al, 2004;Divinski et al, 2004).…”