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Front. Mol. Biosci. | doi: 10.3389/fmolb.2018.00100

Disordered peptides looking for their native environment: Structural basis of CB1 endocannabinoid receptor binding to pepcans

 Alessandro Emendato1, Remo Guerrini2, Erika Marzola2,  Hans Wienk3,  Rolf Boelens3,  Serena Leone1* and  Delia Picone1*
  • 1Università degli Studi di Napoli Federico II, Italy
  • 2University of Ferrara, Italy
  • 3Utrecht University, Netherlands

Endocannabinoid peptides, or “pepcans”, are endogenous ligands of the CB1 cannabinoid receptor. Depending on their length, they display diverse activity: For instance, the nona-peptide Pepcan-9, also known as hemopressin, is a powerful inhibitor of CB1, whereas the longer variant Pepcan-12, which extends by only three amino acid residues at the N-terminus, acts on both CB1 and CB2 as an allosteric modulator, although with diverse effects. Despite active research on their pharmacological applications, very little is known about structure-activity relationships of pepcans. Different structures have been proposed for the nonapeptide, which has also been reported to form fibrillar aggregates. This might have affected, the outcome and reproducibility of bioactivity studies. In an attempt of elucidating the determinants of both biological activity and aggregation propensity of Pepcan-9 and Pepcan-12, we have performed their structure characterization in solvent systems characterized by different polarity and pH. We have found that, while disordered in aqueous environment, both peptides display helical structure in less polar environment, mimicking the proteic receptor milieu. In the case of Pepcan-9, this structure is fully consistent with the observed modulation of the CB1. For Pepcan-12, whose allosteric binding site is still unknown, the presented structure is compatible with the binding at one of the previously proposed allosteric sites on CB1. These findings open the way to structure-driven design of selective peptide modulators of CB1.

Keywords: Pepcans, cannabinoid receptor (CB1), endocannabinoid system, hemopressin, structure function relationship, intrinsically unfolded proteins

Received: 20 Sep 2018; Accepted: 26 Oct 2018.

Edited by:

Piero A. Temussi, Università degli Studi di Napoli Federico II, Italy

Reviewed by:

Fred R. Naider, College of Staten Island, United States
Paolo Rovero, Università degli Studi di Firenze, Italy  

Copyright: © 2018 Emendato, Guerrini, Marzola, Wienk, Boelens, Leone and Picone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Serena Leone, Università degli Studi di Napoli Federico II, Napoli, 80138, Campania, Italy,
Prof. Delia Picone, Università degli Studi di Napoli Federico II, Napoli, 80138, Campania, Italy,