Pegvisomant: structure and function

被引：53

作者：

Pradhananga, S ^{[1
]}

Wilkinson, I ^{[1
]}

Ross, RJM ^{[1
]}

机构：

[1] Univ Sheffield, No Gen Hosp, Div Clin Sci, Sheffield S5 7AU, S Yorkshire, England

来源：

JOURNAL OF MOLECULAR ENDOCRINOLOGY | 2002年 / 29卷 / 01期

关键词：

D O I：

10.1677/jme.0.0290011

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Pegvisomant is the pegylated form of mutant growth hormone (132036). B2036 has increased affinity in one binding site and lowered affinity in its second binding site, it has been shown that this molecule still enables dimerisation of the growth hormone receptor at the cell surface but does not allow the necessary conformational changes for signalling. Pegylation decreases the antagonistic activity of 132036, however the rate of clearance of the pegylated B2036 is greatly reduced compared to the unpegylated form. Even though the antagonistic activity of pegvisomant is lower than B2036, the reduced rate of clearance makes it an effective clinical drug for the treatment of conditions such as acromegaly.

引用

页码：11 / 14

页数：4

共 12 条

[1]

CHEN WY, 1994, J BIOL CHEM, V269, P15892

[2] EXPRESSION OF A MUTATED BOVINE GROWTH-HORMONE GENE SUPPRESSES GROWTH OF TRANSGENIC MICE [J].

CHEN, WY ;

WIGHT, DC ;

WAGNER, TE ;

KOPCHICK, JJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (13) :5061-5065

[3] Long-acting growth hormones produced by conjugation with polyethylene glycol [J].

Clark, R ;

Olson, K ;

Fuh, G ;

Marian, M ;

Mortensen, D ;

Teshima, F ;

Chang, S ;

Chu, H ;

Mukku, V ;

CanovaDavis, E ;

Somer, T ;

Cronin, M ;

Winkler, M ;

Wells, JA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (36) :21969-21977

[4]

CUNNINGHAM BC, 1998, Patent No. 5849535

[5] HUMAN GROWTH-HORMONE AND EXTRACELLULAR DOMAIN OF ITS RECEPTOR - CRYSTAL-STRUCTURE OF THE COMPLEX [J].

DEVOS, AM ;

ULTSCH, M ;

KOSSIAKOFF, AA .

SCIENCE, 1992, 255 (5042) :306-312

[6] The human growth hormone antagonist B2036 does not interact with the prolactin receptor [J].

Goffin, V ;

Bernichtein, S ;

Carrière, O ;

Bennett, WF ;

Kopchick, JJ ;

Kelly, PA .

ENDOCRINOLOGY, 1999, 140 (08) :3853-3856

[7] Growth hormone (GH) and a GH antagonist promote GH receptor dimerization and internalization [J].

Harding, PA ;

Wang, XZ ;

Okada, S ;

Chen, WY ;

Wan, W ;

Kopchick, JJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (12) :6708-6712

[8] AFFINITY MATURATION OF HUMAN GROWTH-HORMONE BY MONOVALENT PHAGE DISPLAY [J].

LOWMAN, HB ;

WELLS, JA .

JOURNAL OF MOLECULAR BIOLOGY, 1993, 234 (03) :564-578

[9] Studies with a growth hormone antagonist and dual-fluorescent confocal microscopy demonstrate that the full-length human growth hormone receptor, but not the truncated isoform, is very rapidly internalized independent of Jak2-Stat5 signaling [J].

Maamra, M ;

Finidori, J ;

Von Laue, S ;

Simon, S ;

Justice, S ;

Webster, J ;

Dower, S ;

Ross, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (21) :14791-14798

[10] Binding and functional studies with the growth hormone receptor antagonist, B2036-PEG (pegvisomant), reveal effects of pegylation and evidence that it binds to a receptor dimers [J].

Ross, RJM ;

Leung, KC ;

Maamra, M ;

Bennett, W ;

Doyle, N ;

Waters, MJ ;

Ho, KKY .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2001, 86 (04) :1716-1723

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