AUTHOR=Ciccone Roselia , Piccialli Ilaria , Grieco Paolo , Merlino Francesco , Annunziato Lucio , Pannaccione Anna 

TITLE=Synthesis and Pharmacological Evaluation of a Novel Peptide Based on Anemonia sulcata BDS-I Toxin as a New KV3.4 Inhibitor Exerting a Neuroprotective Effect Against Amyloid-β Peptide

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00479

DOI=10.3389/fchem.2019.00479

ISSN=2296-2646

ABSTRACT=<p>There is increasing evidence that the fast-inactivating potassium current I<sub>A</sub>, encoded by K<sub>V</sub>3. 4 channels, plays an important role in Alzheimer's Disease (AD), since the neurotoxic β-amyloid peptide1-42 (Aβ<sub>1−42</sub>) increases the I<sub>A</sub> current triggering apoptotic processes. The specific inhibition of K<sub>V</sub>3.4 by the marine toxin extracted from <italic>Anemonia sulcata</italic>, named blood depressing substance-I (BDS-I), reverts the Aβ peptide-induced cell death. The aim of the present study was to identify the smallest fragments of BDS-I, obtained by peptide synthesis, able to inhibit K<sub>V</sub>3.4 currents. For this purpose, whole-cell patch clamp technique was used to evaluate the effects of BDS-I fragments on K<sub>V</sub>3.4 currents in CHO cells heterologously expressing K<sub>V</sub>3.4. We found that BDS-I[1-8] fragment, containing the N-terminal octapeptide sequence of full length BDS-I, was able to inhibit K<sub>V</sub>3.4 currents in a concentration dependent manner, whereas the scrambled sequence of BDS-I[1-8] and all the other fragments obtained from BDS-I full length were ineffective. As we demonstrated in a previous study, BDS-I full length is able to counteract Aβ<sub>1−42</sub>-induced enhancement of K<sub>V</sub>3.4 activity, preventing Aβ<sub>1−42</sub>-induced caspase-3 activation and the abnormal nuclear morphology in NGF-differentiated PC-12 cells. Similarly to BDS-I, we found that BDS-I[1-8] blocking K<sub>V</sub>3.4 currents prevented Aβ<sub>1−42</sub>-induced caspase-3 activation and apoptotic processes. Collectively, these results suggest that BDS-I[1-8] could represent a lead compound to be developed as a new drug targeting K<sub>V</sub>3.4 channels.</p>