Glycoprotein hormone structure-function and analog design

Irving Boime, David Ben-Menahem

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Human chorionic gonadotropin (hCG), luteinizing hormone, follicle- stimulating hormone (FSH), and thyrotropin (TSH) are hormones that share a common α subunit but differ in their β subunits. Recombinant DNA techniques, valuable tools for structure-function analyses, provide an approach for designing therapeutic analogs. FSH is used clinically to stimulate the ovarian follicles for in vitro fertilization and to initiate follicular maturation in women with infertility problems. The CGβ subunit contains a carboxy-terminal extension (CTP) with four serine O-linked oligosaccharides, which is important for the long half-life of hCG. A clinical problem of FSH is its relatively short half-life in circulation. Fusing CTP to the FSHβ coding sequence increased the in vivo potency of the resulting FSH dimer over three-fold. Analogs of the other hormones containing CTP also increase their biologic half-life. Subunit assembly is vital to the function of these hormones. To address whether α and β subunits can be synthesized as one chain and also maintain biological activity, a chimera comprised of the hCG β subunit genetically fused to the α subunit was constructed. The resulting polypeptide was efficiently secreted and displayed an increased biologic activity in vitro and in vivo. Similarly, the single- chain form of FSH also retained in vivo activity. Since subunit dissociation inactivates the activity of the heterodimer, single-chain analogs should have longer biological half-lives. These analogs represent suitable substrates for engineering potent and stable agonists and antagonists.

Original languageEnglish
Pages (from-to)271-289
Number of pages19
JournalRecent Progress in Hormone Research
Volume54
StatePublished - 1 Dec 1999
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology

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