2. Academic Validation
  3. From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action

From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action

  • Eur J Med Chem. 2020 Oct 15;204:112481. doi: 10.1016/j.ejmech.2020.112481.
Quy T N Tran 1,  Daniel W S Tan 2,  W S Fred Wong 3,  Christina L L Chai 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore. Electronic address: A0099426@u.nus.edu.
  • 2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore. Electronic address: phctanw@nus.edu.sg.
  • 3 Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 117600, Singapore; Immunology Program, Life Science Institute, National University of Singapore, 117456, Singapore; SHARE, Molecular Mechanisms of Inflammatory Disease Interdisciplinary Research Group, Singapore; Drug Discovery and Optimization Platform, Medical Science Cluster, Yong Loo Lin School of Medicine, National University Health System, Singapore. Electronic address: phcwongf@nus.edu.sg.
  • 4 Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543, Singapore; Drug Discovery and Optimization Platform, Medical Science Cluster, Yong Loo Lin School of Medicine, National University Health System, Singapore. Electronic address: phacllc@nus.edu.sg.
PMID: 32712435 DOI: 10.1016/j.ejmech.2020.112481
Abstract

Covalent drugs with prolonged actions often show superior potency, yet integrated strategies for optimizing their structural and electronic features are lacking. Herein, we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical and biological conditions. The cell-based SAR studies permitted the assessment of the inhibitor efficacy in more complex systems, which were often limited in traditional covalent drug development using isolated proteins or Peptides. Our in vitro study identified enone 17 as the most promising candidate which demonstrated potent anti-inflammatory activity and superior safety profiles as compared to the lead compound andrographolide. Its reversibility following a Michael addition reaction with biological thiols resulted in more predictable pharmacological responses. In addition, 17 exhibited good in vivo efficacy at doses as low as 0.3 mg/kg when tested in LPS-induced acute lung injury model. Given a good balance of chemical reactivity and biological potency, enone 17 potentially offers a new therapeutic option based on natural product chemistry for the management of inflammatory conditions.

Keywords

Andrographolide; Anti-inflammatory; Covalent inhibitor; Michael addition; Reversibility.

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