Preparation of Superactive Prolactin Receptor Antagonists

Gili Solomon, Ewa Oclon, Zvi Hayouka, Arieh Gertler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Most breast cancer deaths are caused by malignant estrogen receptor-positive breast tumors that later recur as metastatic disease. Prolactin (PRL) has been documented as a factor promoting breast cancer development and metastasis. We therefore developed superactive prolactin receptor (PRLR) antagonists aimed at blocking PRL action. We purified 12 novel mutants to homogeneity as monomers, and the most potent antagonist was over 95-fold more active than the previously reported weak antagonist, the mutant Del 1-9 human PRL G129R. This enhanced antagonistic activity resulted mostly from prolonged interaction with the extracellular domain (ECD) of PRLR. All mutants were properly refolded, as indicated by interaction with human PRLR-ECD and by circular dichroism analysis. We then prepared monopegylated variants of the most active mutants to extend their biological half-life in vivo.

Original languageAmerican English
Article numberbqac186
JournalEndocrinology
Volume164
Issue number1
DOIs
StatePublished - 1 Jan 2023

Bibliographical note

Publisher Copyright:
© 2022 The Author(s).

Keywords

  • antagonist
  • human
  • prolactin
  • receptor
  • super-active

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