While acute inflammation is a short-term adaptive response to harmful stimuli, chronic inflammation is prolonged, dysregulated and deleterious, and is implicated in the pathogenesis of many diseases including asthma, arthritis, and cancer, as well as in neurodegenerative and cardiovascular diseases. Multiple pro-inflammatory, immunomodulatory and pro-resolving signaling cascades orchestrate inflammation. Targeting cyclooxygenases by non-steroidal anti-inflammatory drugs (NSAIDs) is one strategy to relieve inflammation, though long-term use of NSAIDs is afflicted with severe side effects. Hence, the social and economic burden of inflammation-associated pathologies emphasizes the high need for new efficient and safe anti-inflammatory drugs.
Single-target inhibitors block key nodes within the complex lipid mediator networks but fail in adjusting homeostasis. To circumvent the resulting side effects, drug candidates should selectively interfere with pro-inflammatory lipid mediator biosynthesis through multiple targets without suppressing the resolution of inflammation. Recent focus has been placed on dual inhibition of microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO). However, despite continuous efforts from pharmaceutical companies or academic groups, such dual inhibitors have not yet reached the market and their impact on resolution is enigmatic.
Our consortium recently found that human endogenous vitamin E metabolites (LCMs) - and a broad spectrum of semisynthetic analogues – limit inflammation by targeting 5-LO while increasing the systemic levels of the pro-resolving lipid mediator resolvin E3. We also showed, by combining docking and mutational studies that this class of derivatives binds to 5-LO in a unique allosteric pocket, which is structurally similar to the mPGES-1 active site. In fact, we later identified mPGES-1 as subordinate target of d-garcinoic acid and other LCM-inspired lead compounds. LCMs are orally available, relieve inflammation in animal models of peritonitis and asthma, and promote wound healing.
DIVE is a 3-years transdisciplinary project relying on the expertise of six partners from France (natural products chemistry), Germany and Italy (pharmacology), and Austria (molecular modelling). Its final goal is to develop LCM-inspired tocotrienol (T3) analogues as orally available, dual 5-LO/mPGES-1 inhibitors, with favorable ADME properties, able to suppress inflammation in vivo without impeding resolution.
SAR studies on our in-house T3 library (>100 T3 analogues) revealed key structural features of potent 5-LO inhibitors (IC50 < 50 nM) that were included in the virtual workflow to design a first series of dual mPGES-1/5-LO inhibitors. DIVE will initially focus on their synthesis and in parallel evaluate the T3 library for mPGES-1 inhibition. These results, associated to those obtained with the first series, will support the rational design of structurally optimized dual ligands. In silico ADME properties prediction will help prioritizing the compounds prior to synthesis. Comprehensive pharmacological studies on lipid mediator biosynthetic enzymes, primary human immune cells, human blood and biochip-based human organoids will address potency, selectivity, bioavailability, metabolism, pharmacokinetics and subcellular/tissue distribution of the T3 analogues in vitro. Selected lead compounds will be further studied in murine experimental peritonitis and asthma in vivo.
DIVE thus fosters the development of a novel class of anti-inflammatory compounds that selectively inhibits pro-inflammatory lipid mediator biosynthesis without suppressing or even promoting resolution. These anti-inflammatory LCM-inspired drug candidates are in first line dedicated to the treatment of prevalent inflammatory disorders such as asthma and rheumatoid arthritis.
Monsieur Jean-Jacques HELESBEUX (SUBSTANCES D'ORIGINE NATURELLE ET ANALOGUES STRUCTURAUX)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
SONAS SUBSTANCES D'ORIGINE NATURELLE ET ANALOGUES STRUCTURAUX
Friedrich-Schiller-Universität / Department of Pharmaceutical/Medicinal Chemistry
INSPIRE Jena Jena University Hospital / Center for Sepsis Control and Care, Research Group INSPIRE
University of Naples Federico II / Department of Experimental Pharmacology / Department of Pharmacy
Paracelsus Medical University / Department of Pharmaceutical and Medicinal Chemistry
Center for Chemistry and Biomedicine - University of Innsbruck / Institute of pharmacy
Help of the ANR 244,404 euros
Beginning and duration of the scientific project: May 2020 - 36 Months