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NEUROPHARMACOLOGY

Ethanol Antagonist Peptides: Structural Specificity without Stereospecificity

Neurology Service, Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts (M.F.W., C.E.M., M.E.C.); Department of Neurology, Harvard Medical School, Boston, Massachusetts (M.F.W., C.E.M., M.E.C.); Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts (M.F.W., C.E.M., M.E.C.); and the University of North Carolina Bowles Center for Alcohol Studies and Department of Cell and Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina (S.-y.C., K.K.S.)

Increasing evidence suggests that ethanol damages the developing nervous system partly by disrupting the L1 cell adhesion molecule. Ethanol inhibits L1-mediated cell adhesion, and compounds that antagonize this action also prevent ethanol-induced embryotoxicity. Two such compounds are the small peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL). We showed previously that NAP and SAL antagonize ethanol inhibition of L1 adhesion at femtomolar to picomolar concentrations. Here we demonstrate that, despite this extraordinary potency, both NAP and SAL lack stereospecificity. D-NAP, a peptide composed entirely of D-amino acids, was an effective ethanol antagonist in NIH/3T3 cells transfected with human L1 and in the NG108-15 neural cell line. Interestingly, Ala-substituted derivatives of D-NAP demonstrate the same structure-activity relation as the corresponding derivatives of L-NAP. The Ser-Ile-Pro motif was important for the ethanol antagonist activity of D-NAP, L-NAP, and L-SAL, with Ile being the most critical element in all three. Like L-NAP, D-NAP effectively reduced ethanol-induced growth retardation in mouse whole embryo culture. The potential resistance of D-peptides to proteases makes D-NAP a potentially attractive agent for the prevention of fetal alcohol syndrome.

Address correspondence to: Dr. Michael E. Charness, Department of Neurology (127), Harvard Medical School, VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, MA 02132. E-mail: mcharness{at}hms.harvard.edu

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