Thrombin rapidly digests adrenomedullin: Synthesis of adrenomedullin analogs resistant to thrombin

Biochem Biophys Res Commun. 2020 Aug 27;529(3):778-783. doi: 10.1016/j.bbrc.2020.06.057. Epub 2020 Jul 19.

Abstract

Human adrenomedullin (AM) functions as a circulating hormone and as a local paracrine mediator with multiple biological activities. We investigated the metabolism of AM by examining its fragmentation in human serum. Adrenomedullin was rapidly cleaved in human serum, but was relatively stable in plasma. We showed that AM was rapidly digested by thrombin in serum, with AM(13-44) as the main product. On the basis of these data, we prepared AM analogs in which Arg-44 was replaced by Ala, Lys, and D-Arg, respectively. These analogs were resistant to thrombin and showed comparable biological activity to native AM. Furthermore, the bioavailabilities of these peptides were improved after subcutaneous administration in rats. These AM analogs may be promising drug candidates for clinical applications.

Keywords: Adrenomedullin; Adrenomedullin analog; Bioavailability; Thrombin; cAMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / chemical synthesis
  • Adrenomedullin / chemistry*
  • Adrenomedullin / metabolism*
  • Adrenomedullin / pharmacokinetics
  • Animals
  • HEK293 Cells
  • Humans
  • Male
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacokinetics
  • Proteolysis
  • Rats, Wistar
  • Thrombin / metabolism*

Substances

  • ADM protein, human
  • Peptide Fragments
  • Adrenomedullin
  • Thrombin