Stabilization of the helical structure of Y2-selective analogues of neuropeptide Y by lactam bridges

Yao, SG; Smith-White, MA; Potter, EK; Norton, RS

Author(s): Yao, SG; Smith-White, MA; Potter, EK; Norton, RS;
Details: Publication Year 2002-05-23,Volume 45,Issue #11,Page 2310-2318
Journal Title: JOURNAL OF MEDICINAL CHEMISTRY
Publication Type: Journal Article
Abstract: The importance of helical structure in an analogue of NPY selective for the Y2 receptor, Ac[Leu(28,31)]NPY24-36, has been investigated by introducing a lactam bridge between positions 28 and 32. The resulting analogue, Ac-cyclo(28/32)[Ala(24), Lys(28),Leu(31),Glu(32)]NPY24-36 is a potent Y2-selective agonist. Structural analysis by NMR shows that this analogue forms a helical structure in a 40% trifluoroethanol/water mixture, whereas in water only the region around the lactam bridge (LyS(28)-Glu(32)) adopts helical-like structure, with both N- and C-termini being poorly defined. The observation of well-defined helical structure in aqueous TFE contrasts with that reported for a similar analogue, Ac-cyclo(28/32)[LyS(28),Glu(32)]Npy(25-36)(Rist et al. FEBS Lett. 1996, 394, 169-173), which consisted of a hairpin-like structure that brought the N- and C-termini into proximity. We have therefore determined the structures of this analogue, as well as those of Ac-cyclo(28)/(32)[Ala(24), Lys(28),Leu(31),Glu(32)]NPY24-36 and Ac-cyclo(28/32)[Ala(24),Lys(28),Glu(32)]-Npy(24-36), under identical solution conditions (30% TFE/H2O mixture at 308 K) and find essentially the same helical structure in all three peptides. These findings support the proposal that these Y2-selective analogues adopt a helical structure when bound to the Y2 receptor.
Publisher: AMER CHEMICAL SOC
Keywords: NUCLEAR-MAGNETIC-RESONANCE; PRESYNAPTIC Y-2 RECEPTOR; CONFORMATIONAL PROPERTIES; PANCREATIC-POLYPEPTIDE; BIOLOGICAL-ACTIVITY; TERMINAL FRAGMENT; SELF-ASSOCIATION; BINDING-AFFINITY; NMR; DYNAMICS
Publisher's Version: https://doi.org/10.1021/jm010543z
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Creation Date: 2002-05-23 12:00:00