http://www.cnr.it/ontology/cnr/individuo/prodotto/ID181800
Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity (Articolo in rivista)
- Type
- Label
- Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity (Articolo in rivista) (literal)
- Anno
- 2005-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1111/j.1399-3011.2005.00207.x (literal)
- Alternative label
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Alessandra Barazza; Angela Wittelsberger; Nereo Fiori; Elisabetta Schievano; Stefano Mammi; Claudio Toniolo; Joseph M. Alexander; Michael Rosenblatt; Evaristo Peggion; Michael Chorev (literal)
- Pagina inizio
- Pagina fine
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
- Rivista
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
- Note
- ISI Web of Science (WOS) (literal)
- Scopu (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
- Univ Padua, Dept Chem Sci, Inst Biomol Chem, CNR, I-35131 Padua, Italy;
Beth Israel Deaconess Med Ctr, Div Bone & Mineral Res, Boston, MA 02215 USA;
Harvard Univ, Sch Med, Boston, MA 02215 USA. (literal)
- Titolo
- Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity (literal)
- Abstract
- The N-terminal 1-34 segment of parathyroid hormone
(PTH) is fully active in vitro and in vivo and it can reproduce all
biological responses in bone characteristic of the native intact PTH.
Recent studies have demonstrated that N-terminal fragments
presenting the principal activating domain such as PTH(1-11) and
PTH(1-14) with helicity-enhancing substitutions yield potent
analogues with PTH(1-34)-like activity. To further investigate the
role of a-helicity on biological potency, we designed and
synthesized by solid-phase methodology the following hPTH(1-11)
analogues substituted at positions 1 and/or 3 by the sterically
hindered and helix-promoting Ca-tetrasubstituted a-amino acids
a-amino isobutyric acid (Aib), 1-aminocyclopentane-1-carboxylic
acid (Ac5c) and 1-aminocyclohexane-1-carboxylic acid (Ac6c): Ac5c-
V-Aib-E-I-Q-L-M-H-Q-R-NH2 (I); Aib-V-Ac5c-E-I-Q-L-M-H-Q-R-NH2
(II); Ac6c-V-Aib-E-I-Q-L-M-H-Q-R-NH2 (III); Aib-V-Ac6c-E-I-Q-L-M-HQ-
R-NH2 (IV); Aib-V-Aib-E-I-Q-L-M-H-Q-R-NH2 (V); S-V-Aib-E-I-Q-LM-
H-Q-R-NH2 (VI), S-V-Ac5c-E-I-Q-L-M-H-Q-R-NH2 (VII); Ac5c-V-S-E-IQ-
L-M-H-Q-R-NH2 (VIII); Ac6c-V-S-E-I-Q-L-M-H-Q-R-NH2 (IX); Ac5c-VAc5c-
E-I-Q-L-M-H-Q-R-NH2 (X); Ac6c-V-Ac6c-E-I-Q-L-M-H-Q-R-NH2
(XI). All analogues were biologically evaluated and
conformationally characterized in 2,2,2-trifluoroethanol (TFE)
solution by circular dichroism (CD). Analogues I-V, which cover the
full range of biological activity observed in the present study, were
further conformationally characterized in detail by nuclear
magnetic resonance (NMR) and computer simulations studies. The
results of ligand-stimulated cAMP accumulation experiments
indicated that analogues I and II are active, analogues III, VI and VII
are very weakly active and analogues IV, V, VIII-XI are inactive. The
most potent analogue, I exhibits biological activity 3500-fold
higher than that of the native PTH(1-11) and only 15-fold weaker
than that of the native sequence hPTH(1-34). Remarkably, the two
most potent analogues, I and II, and the very weakly active
analogues, VI and VII, exhibit similar helix contents. These results
indicate that the presence of a stable N-terminal helical sequence
is an important but not sufficient condition for biological activity. (literal)
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