Deamination of vasopressin (AVP) enhances its antidiuretic activity. Moreover, introduction of D-Arg8 instead of its L enantiomer in deamino-vasopressin (dAVP) results in an extremely potent and selective antidiuretic agonist - desmopressin (dDAVP). In this study we describe the synthesis, pharmacological properties and structures of these two potent antidiuretic agonists, and their inverso analogs. The structures of the peptides are studied in micellar and liposomic models of cell membrane using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy supported by molecular dynamics simulations. Our conformational studies have shown that desmopressin in a membrane mimicking environment adopts one of the characteristic for vasopressin-like peptides β-turn - in position 3,4. Furthermore, dDAVP shows the tendency to create a β-turn in the Cys6-Gly9 C-tail, considered to be important for the antidiuretic activity, and also some tendency to adopt a 5,6 β-turn. In desmopressin, in contrast to the native vasopressin, deamino-vasopressin and [D-Arg8]-vasopressin (DAVP), the Arg8 side chain, crucial for the pressor and antidiuretic activities, is very well exposed for interaction with the receptor, whereas Gly9, crucial for the pressor and uterotonic activities, is situated together with the C-terminal amide group very close to the tocin ring. The arrangements of the Gln4 and Asn5 side chains, being crucial for OT activity, also differ in desmopressin as compared to those of AVP, dAVP and DAVP. These differences in arrangement of the important for activities side chains are likely to explain extremely potent and selective antidiuretic activities of desmopressin. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 245-259, 2016.

• Klíčová slova
• anionic-zwitterionic micelles, deamino-vasopressin, desmopressin, inverso analogs, liposomes,
• MeSH
• 1,2-dipalmitoylfosfatidylcholin chemie   MeSH
• antidiuretika chemická syntéza   farmakologie   MeSH
• cyklizace MeSH
• desmopresin chemická syntéza   farmakologie   MeSH
• fluoreny chemie   MeSH
• fosfatidylglyceroly chemie   MeSH
• liposomy chemie   MeSH
• micely MeSH
• nukleární magnetická rezonance biomolekulární MeSH
• potkani Wistar MeSH
• sekundární struktura proteinů MeSH
• simulace molekulární dynamiky MeSH
• techniky syntézy na pevné fázi metody   MeSH
• uterotonika chemická syntéza   farmakologie   MeSH
• uterus účinky léků   fyziologie   MeSH
• vodíková vazba MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,2-dipalmitoylfosfatidylcholin MeSH
• 1,2-dipalmitoylphosphatidylglycerol MeSH Prohlížeč
• antidiuretika MeSH
• desmopresin MeSH
• fluoreny MeSH
• fosfatidylglyceroly MeSH
• liposomy MeSH
• micely MeSH
• uterotonika MeSH

We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [D-Arg(8)]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides β-turns: in the 2-5 and 3-6 fragments. The inverso-analogues also adopt β-turns in the 3-6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr(2), Phe(3), and Arg(8), important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr(2) and Phe(3) in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide-membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic-zwitterionic liposomes as well as the anionic-zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones.

• Klíčová slova
• Anionic–zwitterionic micelles, Antidiuretic agonists, Inverso analogues, Liposomes,
• MeSH
• antidiuretika chemická syntéza   chemie   farmakologie   MeSH
• arginin vasopresin analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• buněčná membrána chemie   účinky léků   MeSH
• krysa rodu Rattus MeSH
• liposomy chemie   MeSH
• micely * MeSH
• molekulární sekvence - údaje MeSH
• peptidy chemie   MeSH
• potkani Wistar MeSH
• sekvence aminokyselin MeSH
• simulace molekulární dynamiky * MeSH
• terciární struktura proteinů MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antidiuretika MeSH
• arginin vasopresin MeSH
• liposomy MeSH
• micely * MeSH
• peptidy MeSH