Potent antidiuretic agonists, deamino-vasopressin and desmopressin, and their inverso analogs: NMR structure and interactions with micellar and liposomic models of cell membrane

Emilia Lubecka , Emilia Sikorska , Dariusz Sobolewski , Adam Prahl , Jiřina Slaninová , Jerzy Ciarkowski


Deamination of vasopressin (AVP) enhances its antidiu- retic activity. Moreover, introduction of D-Arg8 instead of its L enantiomer in deamino-vasopressin (dAVP) results in an ext remely 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 mem- brane using CD spectroscopy. Additionally, three- dimensiona l st ructures 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 b-turn - in position 3,4. Fur- ther more, dDAVP shows the tendency to create a b-turn in the Cys6-Gly9 C-tail, considered to be important for the antidiuretic activity, and also some tendency to adopt a 5,6 b-turn. In desmopressin, in contrast to the native vasopressin, deamino-vasopressin and [D-Arg8]-vasopres- sin (DAVP), the Arg8 side chain, crucial for the pressor and antidiuretic activities, is very well exposed for interac- tion 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 cru- cial for OT activity, also differ in desmopressin as com- pared 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 antidi- uretic activities of desmopressin. V C 2016 Wiley Periodicals, Inc.
Author Emilia Lubecka (FCh / DTCh / LMM)
Emilia Lubecka,,
- Laboratory of Molecular Modeling
, Emilia Sikorska (FCh / DOCh / PBSB)
Emilia Sikorska,,
- Pracownia Badań Strukturalnych Biopolimerów
, Dariusz Sobolewski (FCh / DOCh / LChB)
Dariusz Sobolewski,,
- Laboratory of Chemistry of Biopolymers
, Adam Prahl (FCh / DOCh / LChB)
Adam Prahl,,
- Laboratory of Chemistry of Biopolymers
, Jiřina Slaninová - [Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic]
Jiřina Slaninová,,
, Jerzy Ciarkowski (FCh / DTCh / LMM)
Jerzy Ciarkowski,,
- Laboratory of Molecular Modeling
Journal seriesBiopolymers, ISSN 0006-3525, e-ISSN 1097-0282, (A 25 pkt)
Issue year2016
Publication size in sheets0.7
Keywords in Englishdesmopressin, deamino-vasopressin, anionic-zwitterionic micelles, liposomes, inverso
ASJC Classification1605 Organic Chemistry; 2502 Biomaterials; 1303 Biochemistry; 2700 General Medicine; 1304 Biophysics
URL http://onlinelibrary.wiley.com/doi/10.1002/bip.22825/epdf
Languageen angielski
Score (nominal)25
Score sourcejournalList
ScoreMinisterial score = 25.0, 07-02-2020, ArticleFromJournal
Ministerial score (2013-2016) = 25.0, 07-02-2020, ArticleFromJournal
Publication indicators WoS Citations = 0; Scopus Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 0.723; WoS Impact Factor: 2016 = 1.908 (2) - 2016=2.225 (5)
Citation count*1 (2020-02-14)
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