The endogenous hormone oxytocin is produced in the hypothalamus and secreted into the bloodstream by the posterior pituitary gland. It exhibits a variety of biological effects on contractile and membrane transport phenomena. The oxytocin sequence is [Cys1-Tyr2-Ile3-Gln4-Asn5-Cys6]-Pro7-Leu8-Gly9-NH2. Between two cysteines moieties is the disulphide bridge characterized as a cross β structure, with the H-bonded ring being closed by NH of asparagine5 and C=O of tyrosine2. A second β turn was proposed, comprised of residue 6-9--, and utilizing C=O of cysteine6 and NH of glycine9 to close the H-bonded ring of the β-turn. The proposed orientation of the peptide moiety that constitutes the end of both β-turns agree with the X-ray crystallographic data on ferrichrome-A and follows similar conformations occurring in lysozyme. The other β-turn is further stabilized by H bonding of NH of leucine8 to C=O of asparagine5, the end of the peptide. These two β turns are the point of departure for miscellaneous considerations comprising how the differential biological properties of naturally occurring neurohypophy seal peptides and particularly their synthetic congeners can be envisioned. The disulphide bridge plays important role in the structure, stability, and biological function of endogenous peptides or proteins, however, mentioned S-S bond is unstable in reducing conditions, so it was replaced by stable [1,2,3]triazolyl moiety. In fact, the triazoles were selected for replacing the disulphide bond because of their high dipole moment, chemical orthogonality, conformational stability. With the aim to develop more stable nonapeptide drugs targeting the OT receptor (OXTR),we designed a series of click analogs of oxytocin that vary in the size of the bridge and the location and orientation of the [1,2,3]triazolyl moiety within this bridge to study the effects on the interaction with receptor by by molecular dynamics (MD) simulations. In this content the Cys1 and Cys6 located in the native hormone were exchanged with Nα-Fmoc-ω-azido-α-amino acids and Nα-Fmoc-ω-ynoic-α-amino acids with different length of the side chain azido forming [1,2,3]triazolyl ring via mechanism of Huisgen cycloaddition.

. Design and synthesis of clicked oxytocin analogs / A. Staśkiewicz, L. Macchia, F. Nuti, M. Jewgiński, M.Larregola, M. Chorev, P. Rovero, A.M. Papini, R. Latajka. - STAMPA. - (2019), pp. 35-35. (Intervento presentato al convegno 25th Polish Peptide Symposium).

. Design and synthesis of clicked oxytocin analogs.

L. Macchia;F. Nuti;P. Rovero;A. M. Papini;
2019

Abstract

The endogenous hormone oxytocin is produced in the hypothalamus and secreted into the bloodstream by the posterior pituitary gland. It exhibits a variety of biological effects on contractile and membrane transport phenomena. The oxytocin sequence is [Cys1-Tyr2-Ile3-Gln4-Asn5-Cys6]-Pro7-Leu8-Gly9-NH2. Between two cysteines moieties is the disulphide bridge characterized as a cross β structure, with the H-bonded ring being closed by NH of asparagine5 and C=O of tyrosine2. A second β turn was proposed, comprised of residue 6-9--, and utilizing C=O of cysteine6 and NH of glycine9 to close the H-bonded ring of the β-turn. The proposed orientation of the peptide moiety that constitutes the end of both β-turns agree with the X-ray crystallographic data on ferrichrome-A and follows similar conformations occurring in lysozyme. The other β-turn is further stabilized by H bonding of NH of leucine8 to C=O of asparagine5, the end of the peptide. These two β turns are the point of departure for miscellaneous considerations comprising how the differential biological properties of naturally occurring neurohypophy seal peptides and particularly their synthetic congeners can be envisioned. The disulphide bridge plays important role in the structure, stability, and biological function of endogenous peptides or proteins, however, mentioned S-S bond is unstable in reducing conditions, so it was replaced by stable [1,2,3]triazolyl moiety. In fact, the triazoles were selected for replacing the disulphide bond because of their high dipole moment, chemical orthogonality, conformational stability. With the aim to develop more stable nonapeptide drugs targeting the OT receptor (OXTR),we designed a series of click analogs of oxytocin that vary in the size of the bridge and the location and orientation of the [1,2,3]triazolyl moiety within this bridge to study the effects on the interaction with receptor by by molecular dynamics (MD) simulations. In this content the Cys1 and Cys6 located in the native hormone were exchanged with Nα-Fmoc-ω-azido-α-amino acids and Nα-Fmoc-ω-ynoic-α-amino acids with different length of the side chain azido forming [1,2,3]triazolyl ring via mechanism of Huisgen cycloaddition.
2019
25th Polish Peptide Symposium, Wojanów (Poland)
25th Polish Peptide Symposium
Goal 3: Good health and well-being for people
A. Staśkiewicz, L. Macchia, F. Nuti, M. Jewgiński, M.Larregola, M. Chorev, P. Rovero, A.M. Papini, R. Latajka
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1204505
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