tailieunhanh - Báo cáo Y học: Conformationally constrained human calcitonin (hCt) analogues reveal a critical role of sequence 17–21 for the oligomerization state and bioactivity of hCt

Calcitonin (Ct) is a 32-residue peptide hormone that is mainly known for its hypocalcemic effect and the inhibition of bone resorption. Our previous studies have led to potent, side-chain lactam-bridged human Ct (hCt) analogues [Kapurniotu, A. Kayed, R., Taylor, . & Voelter W. (1999) Eur. J. , 606±618; Kapurniotu, A. & Taylor, . (1995)J. Med. , 836±847]. We have hypothesized that a possibly type Ibturn/bsheet confor-mation in the region 17±21 may play an important role in hCt bioactivity. . | Eur. J. Biochem. 269 780-791 2002 FEBS 2002 Conformationally constrained human calcitonin hCt analogues reveal a critical role of sequence 17-21 for the oligomerization state and bioactivity of hCt Athanasios Kazantzis1 Michaela Waldner1 John W. Taylor2 and Aphrodite Kapurniotu1 1 Physiological-chemical Institute Department of Physical Biochemistry University of Tubingen Germany 2Rutgers University Department of Chemistry and Chemical Biology Piscataway NJ USA Calcitonin Ct is a 32-residue peptide hormone that is mainly known for its hypocalcemic effect and the inhibition of bone resorption. Our previous studies have led to potent side-chain lactam-bridged human Ct hCt analogues Kapurniotu. A. Kayed R. Taylor . Voelter W. 1999 Eur. J. Biochem. 265 606-618 Kapurniotu A. Taylor . 1995 J. Med. Chem. 38 836-847 . We have hypothesized that a possibly type I p turn p sheet conformation in the region 17-21 may play an important role in hCt bioactivity. To investigate this hypothesis analogues of the potent hCt agonist cyclo17 21- Asp17 Lys21 hCt 1 bearing type I and IT orII p turn-promoting substituents at positions 18 and 19 were designed synthesized and their solution conformations human Ct receptor binding affinities and in vivo hypocalcemic potencies were assessed. The novel analogues include cyclo17 21- Asp17 D-Phe19 Lys21 hCt 2 cyclo17 21- Asp17 Aib18 Lys21 hCt 3 cyclo17 21- Asp17 D-Lys18 Lys21 hCt 4 corresponding partial sequence peptides containing the lactam-bridged region 16-22 and nonbridged control peptides. Only 1 showed a higher Ct receptor binding affinity than hCt whereas analogues 2-4 had similar receptor affinities to hCt. In the in vivo hypocalcemic assay 3 and 4 were as potent as 1 whereas 2 completely lost the high potency of 1 suggesting that type I and II p turn-promoting substituents are fully compatible with in vivo bioactivity. CD spectroscopy showed that analogues 1-4 were markedly p sheet-stabilized compared to hCt and indicated the .

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