Synthesis and biological activity of oxytocin analogues containing unnatural amino acids in position 9: structure activity study

Magafa, Vassiliki; Borovičková, Lenka; Slaninová, Jiřina; Cordopatis, Paul

doi:10.1007/s00726-009-0372-2

Cited by 9 publications

(7 citation statements)

References 45 publications

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“…This result suggests that the second residue should be highly hydrophobic or have relatively large side chains, which are important for antagonist activity. As reported by Magafa et al, substitutions at the P2 residue to D-Tyr (Et) or D-1-Nal become strong antagonists . This indicates that the aromatic ring of the P2 residue is essential for the antagonist activity.…”

Section: Discussionmentioning

confidence: 55%

“…The P2 residue variant substituted with Leu (Y2L) and the P4, P5, and P7 residue variants substituted with Phe (Q4F, N5F, P7F) exhibited antagonistic activity. Given that some researchers reported the antagonistic activity of the P2 residue substituent, , we then performed a detailed evaluation of the activity of the P2 residue variants.…”

Section: Resultsmentioning

confidence: 99%

“…As reported by Magafa et al, substitutions at the P2 residue to D-Tyr (Et) or D-1-Nal become strong antagonists. 26 This indicates that the aromatic ring of the P2 residue is essential for the antagonist activity. This coincides with the results obtained.…”

Section: ■ Discussionmentioning

confidence: 99%

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Agonist/Antagonist Activity of Oxytocin Variants Obtained from Free Cyclic Peptide Libraries Generated via Amino Acid Substitution

et al. 2021

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We established a method for synthesizing a free cyclic peptide library via peptide array synthesis to demonstrate the sequence activity of cyclic peptides. Variants of the cyclic nonapeptide oxytocin (OXT) were synthesized via residue substitution. Natural amino acids (AAs) were classified into eight groups based on their physical properties and the size of their side chains, and a representative AA from each group was selected for residue substitution. All OXT variants were systematically evaluated for agonist/ antagonist activity. Consequently, no improvement in agonist activity was observed, although substitution of the P4 and P8 residues resulted in decreased activity due to AA substitution. A few OXT variants exhibited antagonistic activity. In particular, the variants with P2 Leu residue substitution (Y2L) and Phe substitutions at residues 4 (Q4F), 5 (N5F), and 7 (P7F) showed high antagonistic activity. Variant Y2W was found to have the highest inhibitory effect, with a dissociation constant of 44 nM, which was comparable to that of the commercial antagonist atosiban (21 nM). Therefore, a free cyclic peptide library constructed via substitution with a natural AA residue was confirmed to be a powerful tool for bioactive peptide screening.

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Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 99%

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Agonist/Antagonist Activity of Oxytocin Variants Obtained from Free Cyclic Peptide Libraries Generated via Amino Acid Substitution

et al. 2021

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“…Here, we focus on the properties of the most widely used peptides requested from the Manning laboratory or purchased from suppliers, together with some recently reported potential clinically useful peptides from the Ferring Laboratory (38, 39). Space considerations preclude our being able to present or to discuss recent synthetic studies carried out in other laboratories (40–43). We also update the current status of the pre‐clinical and clinical development of nonpeptide AVP and OT antagonists and of the pre‐clinical development of nonpeptide OT agonists (44).…”

Section: Scope Of the Present Reviewmentioning

confidence: 99%

Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

Manning

Misicka

Olma

et al. 2012

J Neuroendocrinology

372

348

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We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V1a, V1b and V2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V2/V1a antagonist, conivaptan and the V2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V1a, V1b and V2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.

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“…Considerando-se que as características da estrutura ou do "backbone" de um peptídeo são afetadas pelos ângulos de torção , ,  e  então estes ângulos controlam o espaço conformacional do peptídeo (BARRETT; ELMORE, 1998). A substituição de aminoácidos não naturais em sequências peptídicas reconhecidas por determinados alvos moleculares podem resultar em variações na atividade biológica devido a demandas estéricas ou mudanças conformacionais resultantes da interação dos análogos com o alvo em questão (MAGAFA et al, 2010). A prolina distingue-se por ser um alfa aminoácido natural capaz de conferir rigidez ao ângulo de torção  (chi) (GIBSON et al, 1999).…”

Section: Introductionunclassified

Síntese e ensaio de análogos estruturais de prolina no estudo da interação com trombina.

Silva¹

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SILVA, R. N. Synthesis and assay of structural analogues of proline in the study of interaction with thrombin. 2013. 82 p. Dissertation (Masters thesis in Biotechnology) -Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2013. Thrombin is a serine peptidase that acts as the main agent of the coagulation cascade, with procoagulant properties as well as anticoagulant and antifibrinolytic properties. The activity of thrombin can be inhibited by the binding of inhibitors to its three domains: the active site and its two exosites. The challenge of this work was the use of unnatural amino acids that could be recognized by thrombin and confer hydrolysis resistance when inserted in a given peptide sequence, generating high-affinity inhibitors. Among the 20 natural L-amino acids encoded, proline is the unique amino acid able to confer conformational constraint to the peptide wherein is inserted, and is recognized as a site of hydrolysis by a highly specific subgroup of peptidases denominated prolylpeptidases. Synthetic routes were employed in the functional group attached to the carbon in position 4 of the pyrrolidinic ring of trans-4-hydroxy-L-proline to obtain four proline analogues containing amino and guanidino groups in this position with cis and trans spatial isomerism. Additionally, the 4-guanidino phenylalanine, known by possess characteristics of aromaticity and cationic character, was compared with the analogues of proline in all tests. These amino acids were employed in the synthesis of bivalirudin analogues. Among the thrombin inhibitors presently available on the market, bivalirudin is structurally characterized as an inhibitor of 20 amino acids that can be cleaved at Arg-Pro position and has elements that interact with the active site and exosite I, presenting an inhibition constant between 1.9 ─ 2,3 nM . For a preview check of the interaction between the analogues generated with the active site of thrombin, a computer simulation was performed by molecular docking with each analogue. Assays of competitive inhibition and platelet aggregation have demonstrated that the analogues present inhibitory activity and resistance to hydrolysis when incubated with human thrombin. Among the proline analogues synthesized, the peptide containing trans-4-guanidino-Lproline stood out from the others in competitive inhibition assays, with an inhibition constant of 168 nM. However, the synthesized peptide with the amino acid 4-guanidino-L-phenylalanine presented the highest inhibitory activity in comparison to proline analogues, with an inhibition constant of 6,2 nM. In future works, these analogues of bivalirudin may have the inhibitory effect improved through new changes in the functional groups attached to the proline analogues. Furthermore, modifications can be made to obtain non-peptide analogues in the development of thrombin inhibitors administered orally.

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Synthesis and biological activity of oxytocin analogues containing unnatural amino acids in position 9: structure activity study

Cited by 9 publications

References 45 publications

Agonist/Antagonist Activity of Oxytocin Variants Obtained from Free Cyclic Peptide Libraries Generated via Amino Acid Substitution

Agonist/Antagonist Activity of Oxytocin Variants Obtained from Free Cyclic Peptide Libraries Generated via Amino Acid Substitution

Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

Síntese e ensaio de análogos estruturais de prolina no estudo da interação com trombina.

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