Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds

Brittney A. Klein, Ian M. Robertson, Béla Reiz, Thomas Kampourakis, Liang Li, Brian D. Sykes*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

We have investigated the mechanism and reactivity of covalent bond formation between cysteine-84 of the regulatory domain of cardiac troponin C and compounds containing a nitrile moiety similar to the calcium sensitizer levosimendan. The results of modifications to the levosimendan framework ranged from a large increase in covalent bond formation to complete inactivity. We present the biological activity of one of the most potent compounds. Limitations, including compound solubility and degradation at acidic pH, have prevented thorough investigation of the potential of these compounds. Our studies reveal the efficacious nature of the malononitrile moiety in targeting cNTnC and its potential in future cardiotonic drug design.

Original languageEnglish
Pages (from-to)1007-1012
Number of pages6
JournalAcs Medicinal Chemistry Letters
Volume10
Issue number6
DOIs
Publication statusPublished - 13 Jun 2019

Keywords

  • Cardiac troponin C
  • levosimendan
  • malononitrile
  • reversible thioimidate bond formation

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