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Activity-dependent neuroprotective protein (ADNP) was discovered and first characterized in the laboratory of Prof. Illana Gozes to be regulated by vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) toward neuroprotection. Importantly, ADNP is a master regulator of >400 genes, essential for brain formation, while its haploinsufficiency causes cognitive impairments. Recently,  de novo  mutations in ADNP were identified as leading to the autism-like  ADNP  syndrome, mimicked by the  Adnp -deficient mouse model. Furthermore, novel peptide derivatives of the neuroprotective ADNP-snippet NAP (NAPVSIPQ), developed in our laboratory, include SKIP and the mirroring all D-amino acid SKIP (D-SKIP). We now extended previous evidence suggesting potential antagonistic features for D-SKIP, compared with the neuroprotective peptide SKIP, as was observed by NMR analysis and social/olfactory functional testing. Here, an impact of the  Adnp  genotype was observed in the Morris Water Maze (MWM) test measuring cognition, coupled with improvement by SKIP, opposing the inert/exacerbating effect of D-SKIP. In the elevated plus-maze and open field tests measuring anxiety-related behaviors, contrasting effects of SKIP and D-SKIP were found, with SKIP improving/preserving the normal phenotype of the mouse, and D-SKIP causing alterations. Lastly, an  in silico  analysis suggested that SKIP and D-SKIP bind the microtubule end binding (EB) proteins EB1 and EB3 in different conformations, thereby indicating distinctive natures for the two peptides, potentially mediating differential  in vivo  effects. Altogether, our findings corroborate the notion of D-SKIP acting as an antagonist, thus distinguishing it from the neuroprotective SKIP.

VIP/PACAP-Based Drug Development: The ADNP/NAP-Derived Mirror Peptides SKIP and D-SKIP Exhibit Distinctive in vivo and in silico Effects