Novel super-potent conformationally constrained calcitonin (ct) analogues

Rakez Kayed, W. Faylor, A. Kapurniotu

Research output: Contribution to journalArticle

Abstract

Ct is a hormone of 32 aa known for its hypocalceinic effect. Little is known about the structural features of hCt bioactivity. Recently, we devised a highly potent conformationally constrained bicyclic hCt analogue with the structure (-y(lo7,2 -{Asp17, l,ys21]hCt (1). This analogue exhibited a 20x higher hypocalcemi(: effect than hCt. We hypothesized that a type I 3-turn/-sheet conformation involving residues 17-21 is important for hCt activity. To test this, the slructure of 1 was used as scaffold towards the design of new 3-turn/shoet stabilized analogues. Analogue 2, cyclolT'21-[AspLT, l)-Phe19, Lys21]hCt, designed Io (:ontain a stabilized type II turn, lacked the high hypoealcemic effect of 1. although high ,Lsheet/-turn contents were found by CD. However, analogues 3 and 4, cyclolT'2t-[Asp17, Aibis, Lys21]hCt and cyclolT'21-[Asp17, I)-LysIs, [.ys21]hCt, designed to contain a stabilized type l turn, showed similar poten(:ies to 1. Most importantly, two other superpotent analogues were i(tentified. These analogues showed activities that were either similar to or hiher than those of salmon Ct, which is the most potent known Ct. Together, our results show a strong dependency of hCt bioactivity on the nature and chirality of several residues of hCt sequence (17-21) and demonstrate the importance of a stabilized typo I 3-1urn/Mleet conformation in this region for h() bioactivilv.

Original languageEnglish (US)
JournalFASEB Journal
Volume11
Issue number9
StatePublished - 1997
Externally publishedYes

Fingerprint

calcitonin
Salmon
Calcitonin
Bioactivity
salmon
Conformations
hormones
Hormones
Chirality
Scaffolds
testing
stereoisomerism

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Novel super-potent conformationally constrained calcitonin (ct) analogues. / Kayed, Rakez; Faylor, W.; Kapurniotu, A.

In: FASEB Journal, Vol. 11, No. 9, 1997.

Research output: Contribution to journalArticle

@article{3b761ff19ca442dab76ae5b3854c4b64,
title = "Novel super-potent conformationally constrained calcitonin (ct) analogues",
abstract = "Ct is a hormone of 32 aa known for its hypocalceinic effect. Little is known about the structural features of hCt bioactivity. Recently, we devised a highly potent conformationally constrained bicyclic hCt analogue with the structure (-y(lo7,2 -{Asp17, l,ys21]hCt (1). This analogue exhibited a 20x higher hypocalcemi(: effect than hCt. We hypothesized that a type I 3-turn/-sheet conformation involving residues 17-21 is important for hCt activity. To test this, the slructure of 1 was used as scaffold towards the design of new 3-turn/shoet stabilized analogues. Analogue 2, cyclolT'21-[AspLT, l)-Phe19, Lys21]hCt, designed Io (:ontain a stabilized type II turn, lacked the high hypoealcemic effect of 1. although high ,Lsheet/-turn contents were found by CD. However, analogues 3 and 4, cyclolT'2t-[Asp17, Aibis, Lys21]hCt and cyclolT'21-[Asp17, I)-LysIs, [.ys21]hCt, designed to contain a stabilized type l turn, showed similar poten(:ies to 1. Most importantly, two other superpotent analogues were i(tentified. These analogues showed activities that were either similar to or hiher than those of salmon Ct, which is the most potent known Ct. Together, our results show a strong dependency of hCt bioactivity on the nature and chirality of several residues of hCt sequence (17-21) and demonstrate the importance of a stabilized typo I 3-1urn/Mleet conformation in this region for h() bioactivilv.",
author = "Rakez Kayed and W. Faylor and A. Kapurniotu",
year = "1997",
language = "English (US)",
volume = "11",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "9",

}

TY - JOUR

T1 - Novel super-potent conformationally constrained calcitonin (ct) analogues

AU - Kayed, Rakez

AU - Faylor, W.

AU - Kapurniotu, A.

PY - 1997

Y1 - 1997

N2 - Ct is a hormone of 32 aa known for its hypocalceinic effect. Little is known about the structural features of hCt bioactivity. Recently, we devised a highly potent conformationally constrained bicyclic hCt analogue with the structure (-y(lo7,2 -{Asp17, l,ys21]hCt (1). This analogue exhibited a 20x higher hypocalcemi(: effect than hCt. We hypothesized that a type I 3-turn/-sheet conformation involving residues 17-21 is important for hCt activity. To test this, the slructure of 1 was used as scaffold towards the design of new 3-turn/shoet stabilized analogues. Analogue 2, cyclolT'21-[AspLT, l)-Phe19, Lys21]hCt, designed Io (:ontain a stabilized type II turn, lacked the high hypoealcemic effect of 1. although high ,Lsheet/-turn contents were found by CD. However, analogues 3 and 4, cyclolT'2t-[Asp17, Aibis, Lys21]hCt and cyclolT'21-[Asp17, I)-LysIs, [.ys21]hCt, designed to contain a stabilized type l turn, showed similar poten(:ies to 1. Most importantly, two other superpotent analogues were i(tentified. These analogues showed activities that were either similar to or hiher than those of salmon Ct, which is the most potent known Ct. Together, our results show a strong dependency of hCt bioactivity on the nature and chirality of several residues of hCt sequence (17-21) and demonstrate the importance of a stabilized typo I 3-1urn/Mleet conformation in this region for h() bioactivilv.

AB - Ct is a hormone of 32 aa known for its hypocalceinic effect. Little is known about the structural features of hCt bioactivity. Recently, we devised a highly potent conformationally constrained bicyclic hCt analogue with the structure (-y(lo7,2 -{Asp17, l,ys21]hCt (1). This analogue exhibited a 20x higher hypocalcemi(: effect than hCt. We hypothesized that a type I 3-turn/-sheet conformation involving residues 17-21 is important for hCt activity. To test this, the slructure of 1 was used as scaffold towards the design of new 3-turn/shoet stabilized analogues. Analogue 2, cyclolT'21-[AspLT, l)-Phe19, Lys21]hCt, designed Io (:ontain a stabilized type II turn, lacked the high hypoealcemic effect of 1. although high ,Lsheet/-turn contents were found by CD. However, analogues 3 and 4, cyclolT'2t-[Asp17, Aibis, Lys21]hCt and cyclolT'21-[Asp17, I)-LysIs, [.ys21]hCt, designed to contain a stabilized type l turn, showed similar poten(:ies to 1. Most importantly, two other superpotent analogues were i(tentified. These analogues showed activities that were either similar to or hiher than those of salmon Ct, which is the most potent known Ct. Together, our results show a strong dependency of hCt bioactivity on the nature and chirality of several residues of hCt sequence (17-21) and demonstrate the importance of a stabilized typo I 3-1urn/Mleet conformation in this region for h() bioactivilv.

UR - http://www.scopus.com/inward/record.url?scp=33750130925&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750130925&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:33750130925

VL - 11

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 9

ER -