Drugs from Nature Targeting Inflammation

Vision & Goals

Natural Products in Drug Discovery

For decades drug discovery was successfully fuelled from natural sources. The first blockbuster was developed in the outgoing 19th century starting from salicylic acid, a compound from the willow tree and successfully marketed after derivatisation as aspirin®. A similar successful group of drugs, the statins, originating from Aspergillus terreus (Lovastatin) marks the outgoing 20th century. Analysis of drugs developed between 1981 and 2006 showed that natural products (NPs) or natural product-derived compounds comprised 28% of all new chemical entities (NCEs). In addition, 24% of these NCEs were related to NPs. Although many pharmaceutical companies have discontinued their programs of drug discovery from natural sources and have focused mainly on high-throughput screening of predominantly combinatorial chemistry products throughout the last 10-15 years, the NP field was still contributing to about 50% of all small molecules in the years 2000-2006. This shows that NPs are important and effective sources for new drugs or leads.

Targeting Inflammation

Inflammation is the body's response to tissue injury, either physical (mechanical, irradiation), by infectious agents, or by malignant or altered normal cells. Thus, various and at first glance diverse pathological conditions involve inflammation. These include e.g. arthritis, atherosclerosis, the metabolic syndrome, sepsis, allergies and auto-immune diseases or cancer. For most of these conditions no satisfying treatment of the inflammatory part is available. Effective concepts of prevention are also highly desirable. Inflammation starts with cytokine mediated activation of the vasculature and adhesion and transmigration of leucocytes into the surrounding tissue. Many of the inflammatory processes elicited within the vasculature are regulated by the transcription factor NF-kB. Major target genes of NF-kB include adhesion molecules, cytokines, growth factors, and enzymes, such as COX-2. Most prominent upstream inducers are the pro-inflammatory cytokines, TNF-alpha, IL-1 and bacterial LPS. While it is clear that NF-kB is pivotal for inducing the inflammatory response, much less is known about inhibitory pathways. Important mediators inhibiting NF-kB responses are nuclear receptors among those the glucocorticoid receptor, the peroxisome proliferators-activated receptors (PPARs) the liver X receptor and the orphan nuclear receptors class A4. PPARs are thought to exert their anti-inflammatory activities also by repressing the transactivation of other transcription factors, such as STAT or AP1 proteins, both involved e.g. in the induction of cell adhesion molecules, such as ICAM and VCAM. The consortium will initially focus on well defined molecular targets and pathways involved in inflammation, such as the activating NF-kB pathway and inhibition of inflammation by nuclear receptors (PPARs, LXR, NR4A). In vivo validation and mechanistic studies, however, will be done by cell systems and animal models addressing specifically chronic vascular inflammatory diseases.

Project Aim

The overall aim of the project is the identification and characterisation (chemical and biological/pharmacological) of compounds capable to combat or prevent inflammatory processes specifically in the cardiovascular system. This aim will be approached by a unique combination of strategies:

The focus on NPs (so far approximately 150-200.000 structures are known) representing a structural diversity, that is significantly higher than that of synthetic compounds.

The combination of a molecular/computational approach (target --> pharmacophore modeling --> in silico screening --> in vitro/cell-based pharmacological assays --> animal models/molecular mechanisms) with an empirical/bio-guided approach (knowledge from traditional medicine --> plant selection --> bioassay-guided isolation --> in vitro/cell-based pharmacological assays --> animal models/molecular mechanisms).

This combination of strategies is rendered possible by a consortium of scientists representing expertise in the fields of computational, analytical, and NP chemistry, in vitro screening, cellular signalling, pharmacology, biotechnology and plant conservation as well as cultivation. The consortium is truly interdisciplinary with members from pharmacy, biology, chemistry, veterinarian and human medicine.