000117947 001__ 117947
000117947 005__ 20230519145543.0
000117947 0247_ $$2doi$$a10.1016/j.bioorg.2021.105231
000117947 0248_ $$2sideral$$a127040
000117947 037__ $$aART-2021-127040
000117947 041__ $$aeng
000117947 100__ $$aButrón D.
000117947 245__ $$aDD04107-Derived neuronal exocytosis inhibitor peptides: Evidences for synaptotagmin-1 as a putative target
000117947 260__ $$c2021
000117947 5060_ $$aAccess copy available to the general public$$fUnrestricted
000117947 5203_ $$aThe analgesic peptide DD04107 (Pal-EEMQRR-NH2) and its acetylated analogue inhibit a-calcitonin gene-related peptide (a-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 a-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 a-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 a-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. © 2021
000117947 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000117947 594__ $$a7.1$$b2021
000117947 590__ $$a5.307$$b2021
000117947 592__ $$a0.728$$b2021
000117947 591__ $$aCHEMISTRY, ORGANIC$$b8 / 57 = 0.14$$c2021$$dQ1$$eT1
000117947 593__ $$aBiochemistry$$c2021$$dQ2
000117947 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b99 / 297 = 0.333$$c2021$$dQ2$$eT2
000117947 593__ $$aMolecular Biology$$c2021$$dQ2
000117947 593__ $$aDrug Discovery$$c2021$$dQ2
000117947 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000117947 700__ $$aZamora-Carreras H.
000117947 700__ $$aDevesa I.
000117947 700__ $$aTreviño M.A.
000117947 700__ $$0(orcid)0000-0001-5664-1729$$aAbian O.$$uUniversidad de Zaragoza
000117947 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy A.$$uUniversidad de Zaragoza
000117947 700__ $$aBonache M.Á.
000117947 700__ $$aLagartera L.
000117947 700__ $$aMartín-Martínez M.
000117947 700__ $$aGonzález-Rodríguez S.
000117947 700__ $$aBaamonde A.
000117947 700__ $$aFernández-Carvajal A.
000117947 700__ $$aFerrer-Montiel A.
000117947 700__ $$aJiménez M.Á.
000117947 700__ $$aGonzález-Muñiz R.
000117947 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000117947 773__ $$g115 (2021), 105231$$pBioorg. chem.$$tBioorganic Chemistry$$x0045-2068
000117947 8564_ $$s6160673$$uhttps://zaguan.unizar.es/record/117947/files/texto_completo.pdf$$yVersión publicada
000117947 8564_ $$s2361118$$uhttps://zaguan.unizar.es/record/117947/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000117947 909CO $$ooai:zaguan.unizar.es:117947$$particulos$$pdriver
000117947 951__ $$a2023-05-18-15:41:35
000117947 980__ $$aARTICLE