2. Academic Validation
  3. DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

DD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target

  • Bioorg Chem. 2021 Oct:115:105231. doi: 10.1016/j.bioorg.2021.105231.
Daniel Butrón 1,  Héctor Zamora-Carreras 2,  Isabel Devesa 3,  Miguel A Treviño 2,  Olga Abian 4,  Adrián Velázquez-Campoy 5,  M Ángeles Bonache 1,  Laura Lagartera 1,  Mercedes Martín-Martínez 1,  Sara González-Rodríguez 6,  Ana Baamonde 7,  Asia Fernández-Carvajal 3,  Antonio Ferrer-Montiel 8,  M Ángeles Jiménez 9,  Rosario González-Muñiz 10
Affiliations

Affiliations

  • 1 Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
  • 2 Instituto de Química Física Rocasolano (IQFR-CSIC), Serrano 119, 28006 Madrid, Spain.
  • 3 IDiBE, Universidad Miguel Hernández, Avda. de la Universidad s/n, 03202 Elche, Spain.
  • 4 Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain; Biomedical Research Networking Centre for Liver and Digestive Diseases (CIBERehd), Madrid, Spain; Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain; Aragon Health Sciences Institute (IACS), 50009 Zaragoza, Spain.
  • 5 Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain; Biomedical Research Networking Centre for Liver and Digestive Diseases (CIBERehd), Madrid, Spain; Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain; ARAID Foundation, Government of Aragon, 50018 Zaragoza, Spain.
  • 6 Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain.
  • 7 Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Julián Clavería 6, 33006 Oviedo, Asturias, Spain.
  • 8 IDiBE, Universidad Miguel Hernández, Avda. de la Universidad s/n, 03202 Elche, Spain. Electronic address: aferrer@umh.es.
  • 9 Instituto de Química Física Rocasolano (IQFR-CSIC), Serrano 119, 28006 Madrid, Spain. Electronic address: majimenez@iqfr.csic.es.
  • 10 Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: iqmg313@iqm.csic.es.
PMID: 34388485 DOI: 10.1016/j.bioorg.2021.105231
Abstract

The analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit α-calcitonin gene-related peptide (α-CGRP) exocytotic release from primary sensory neurons. Examining the crystal structure of the SNARE-Synaptotagmin-1(Syt1) complex, we hypothesized that these peptides could inhibit neuronal exocytosis by binding to Syt1, hampering at least partially its interaction with the SNARE complex. To address this hypothesis, we first interrogate the role of individual side-chains on the inhibition of α-CGRP release, finding that E1, M3, Q4 and R6 residues were crucial for activity. CD and NMR conformational analysis showed that linear peptides have tendency to adopt α-helical conformations, but the results with cyclic analogues indicated that this secondary structure is not needed for activity. Isothermal titration calorimetry (ITC) measurements demonstrate a direct interaction of some of these peptides with Syt1-C2B domain, but not with Syt7-C2B region, indicating selectivity. As expected for a compound able to inhibit α-CGRP release, cyclic peptide derivative Pal-E-cyclo[EMQK]R-NH2 showed potent in vivo analgesic activity, in a model of inflammatory pain. Molecular dynamics simulations provided a model consistent with KD values for the interaction of peptides with Syt1-C2B domain, and with their biological activity. Altogether, these results identify Syt1 as a potential new analgesic target.

Keywords

Ala-scan; Analgesia; CGRP; DD04107; Exocytosis; Isothermal titration calorimetry; Molecular modeling; NMR; Synaptotagmin-1.

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