Micelle-bound conformations of neurohypophyseal hormone analogues modified with a Cα-disubstituted residue: NMR and molecular modelling studies

Abstract

In this study, by applying a combined approach of NMR measurements and molecular modelling, the conformations and the interactions with membrane-like environment of five arginine vasopressin (AVP) or oxytocin (OT) analogues modified with Cα-disubstituted cis-1-amino-4-phenylcyclohexane-1-carboxylic acid in position 2 have been determined. In addition, the AVP analogues were prepared in N-acylated forms with various bulky acyl groups. All of the peptides studied interacted with the mixed dodecylphosphocholine:sodium dodecyl sulphate micelle, providing a model of biological membrane. A different polarities of the AVP- and OT-like peptides resulted in their different position relative to the micelle surface. Thus, the arrangement of the former was nearly perpendicular, whereas the latter was rather parallel to the micelle's surface. Moreover, the results of our studies have shown that the binding sites for antagonists may be overlapped with that for agonists, as well as it may be quite different. Nevertheless, the aromatic-aromatic contacts represent the most important interactions for antagonists, whereas the hydrophilic interactions seem to be crucial for agonists.

Structure-based design of glycosylated oxytocin analogues with improved selectivity and antinociceptive activity

“…20,21 Further NMR studies in micelles (both charged and neutral) will be used and compared with previous literature examining OT in nonpolar solvents (e.g., CDCl 3 , DMSO) 41 and in charged micelles. 59 Several of our OT analogues showed increased potency as compared to OT, demonstrating that our modi cations can improve both pharmacodynamic and pharmacokinetic performance. All of the compounds produced no activity at the AVP1a/1b receptors, suggesting that they may be selective in vivo and avoid side effects caused by AVP activation.…”

Structure-Based Design of Glycosylated Oxytocin Analogues with Improved Selectivity and Antinociceptive Activity

“…22,23 Further NMR studies in micelles (both ionic and neutral) will be used and compared with previous literature examining OT in nonpolar solvents (e.g., CDCl 3 , DMSO) 60,61 and in ionic (e.g., SDS) micelles. 62 Several analogues showed increased potency compared to OT, demonstrating that relatively minor modifications can enhance both pharmacodynamic and pharmacokinetic performance. All compounds described here show no activity at the AVP1a/1b receptors, implying that they will be selective in vivo and avoid side effects caused by AVP activation.…”

“…Conformational data of OT in aqueous solution has been published, and the receptor-bound conformation of OT•OTR was recently determined via cryo-EM . The crystal structure of OT bound to OTR has been recently determined via cryo-EM. , Further NMR studies in micelles (both ionic and neutral) will be used and compared with previous literature examining OT in nonpolar solvents (e.g., CDCl 3 , DMSO) , and in ionic (e.g., SDS) micelles …”

Conformations of a model cyclic hexapeptide, CYIQNC:1H-NMR and molecular dynamics studies

“…OT hormone has been known to be of the topic of immense investigation in lieu of its biological functions such as the maintenance of labor and milk ejection in mammals (Gimpl & Fahrenholz, 2001), facilitating the sexual maturation (Parent et al, 2008), stimulating the pre-ovulatory luteinizing hormone surge (Rettori, Canteros, Renoso, Gimeno, & McCann, 1997), and also its biomedical application such as in the treatment of autism (Newschaffer et al, 2007). Toward understanding the biological activities of OT, various works have been reported to be carried out for studying the interactions of OT with neurophysin (Blumenstein, Hruby, Viswanatha, & Chaturvedi, 1984;Eubanks, Lu, Peyton, & Breslow, 1999;Live, Cowburn, & Breslow, 1987;Rose, Wu, Hsiao, Breslow, & Wang, 1996) and with receptor (Bélec, Blankenship, & Lubell, 2005;Budesínsky, Procházka, & Slaninová, 2005;Carnazzi et al, 2001;Lebl et al, 1990;Lubecka, Sikorska, Marcinkowska, & Ciarkowski, 2014;Sikorska & Kwiatkowska, 2013;Turner, Matsoukas, & Moore, 1990).…”