Dual Inhibitors inspired from Vitamin E

Diseases like cancer, cardiovascular disorders and neurodegeneration have a chronic inflammatory component. Immune cells orchestrate these inflammatory processes by producing a variety of lipid mediators that either promote or inhibit the inflammatory reaction or actively terminate inflammation. Non-steroidal anti-inflammatory drugs, like ibuprofen, used in anti-inflammatory therapy, inhibit the formation of prostaglandins, which represent a functional very diverse subgroup of lipid mediators. When taken regularly, these drugs cause severe adverse effects. To minimize risks, current inflammation research aims to specifically lower only the levels of pro-inflammatory lipid mediators. Promising points of attack are 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). We have recently shown that these two enzymes are inhibited by vitamin E metabolites 5-LO much more potent than mPGES-1 while the resolution of inflammation seemed not to be impaired. The aim of the DIVE project is to achieve balanced inhibition of 5-LO and mPGES-1 by manipulating the structure of vitamin E derivatives that naturally occur in plants. Promising drug candidates shall possess a comparable efficacy to non-steroidal anti-inflammatory drugs but have clearly diminished side-effects. To achieve this goal, we will first investigate how structural changes affect the inhibitory potency of vitamin E metabolites. Our drug development strategy includes bioinformatic approaches that predict whether the structure is compatible with oral application and specific target interactions and how the drug candidate binds to the target enzymes. Comprehensive pharmacological studies will then address i) the efficacy of the drug candidate, ii) if it only inhibits the two pro-inflammatory enzymes, as intended, iii) how well it is taken up after oral gavage, iv) how it is distributed in the body and within cells, v) how fast it is secreted, and vi) whether it is enzymatically converted in advance. To answer these questions, we will apply test systems of varying complexity: isolated enzymes, human immune cells, human blood, and biochip-based organoid models. Selected drug candidates will be subjected to animal studies in mice that investigate how effectively and through which mechanism inflammation of the peritoneal cavity and asthma is relieved. Together, our project promises access to a novel class of anti-inflammatory drugs, which selectively inhibit the formation of pro-inflammatory lipid mediators, without impeding the resolution of inflammation or disturbing other central homeostatic processes.

The DIVE project aimed to create a safer class of anti-inflammatory drugs inspired by vitamin E. We wanted to develop dual inhibitors targeting two specific enzymes, 5-lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1. The goal was to make them easy to take orally and effective at reducing inflammation in conditions such as peritonitis and asthma without interfering with the body's natural healing process. We also wanted them to have favorable properties for how the body absorbs, distributes, metabolizes, and excretes them (ADME properties). We identified the detailed structural features that turn vitamin E into potent inhibitors of 5-LOX, mPGES-1, or a balanced combination of both. We also developed derivatives of vitamin E that can be taken orally, reach effective concentrations at target sites in the body, and reduce inflammation in reconstructed human skin and mouse models of inflammation. We discovered specific structures that can switch the response of innate immune cells to stimuli (such as bacterial toxins) from inflammation to resolution. These compounds could suppress the formation of lipid mediators that promote inflammation, while increasing the levels of mediators that counteract inflammation, relieve pain, are thought to actively resolve inflammation, or otherwise modulate the immune system. We also learned how these vitamin E derivatives achieve some of these activities, in part through the movement of a specific enzyme, 15-LOX-1, within cells. We gained a better understanding of how these vitamin E derivatives work in different types of immune cells, under different conditions, and in interactions with other cells. Finally, we expanded the use of these compounds from just fighting inflammation to also protecting against peroxidative damage, which could be useful in treating certain degenerative diseases. Our success was made possible by working closely with national and international partners. Partners in Angers synthesized the vitamin E derivatives, gained insights from computational methods in Salzburg, and provided us with compounds to test and study. Together with partners from Jena, we gave feedback to Angers and helped them design new versions of the compounds, creating a continuous cycle of improvement.