FWF - Metalloproteinase - Development of new matrix metalloproteinase-13 inhibitors

Project: Research project

Description

Osteoarthritis (OA), the degeneration of cartilage, is the most prevalent chronic joint disease in the western world and ranks among the top five causes of physical disability. Despite intensive research over the past years, medical treatment options for OA are still rather limited and are mainly focused on
relieving pain. There is an urgent need for the development of disease modifying agents to increase the quality of life for OA patients. The zinc-dependent matrix metalloproteinase-13 (MMP-13) was identified to be mainly responsible for the cleavage of type II collagen in OA, which leads to the
destruction of articular cartilage. First-generation zinc-chelating inhibitors failed mostly due to dose limiting side effects collectively described as musculoskeletal syndrome. As a consequence compounds, which interact with secondary binding sites (exosites) of MMP-13 and lack zinc-chelating
groups were extensively screened. Especially MMP-13 S1’ subsite binding compounds exhibited promising inhibitor properties and selectivity profiles but none of these have successfully been employed in clinical trials.
A high throughput screening (HTS) campaign using a newly developed triple-helical peptide (THP) fluorescence resonance energy transfer (FRET) assay, was carried out, based on the knowledge about the importance of subsite-binding properties and the resulting intention to identify new exosites which
could be utilized for the design of next-generation inhibitors. THPs represent perfect substrates for the development of non-active site binding and selective MMP inhibition due to their distinct conformational features. THP assays are not limited to the identification MMP-13 inhibitors and therefore, in future studies, the drug design approach described within this proposal, will be extended toward the investigation of non-active site binding inhibitors targeting the remaining human
collagenases (MMP-1, -8 and -14), which play important roles during tumor progression andmetastasis.
Based on the isolation of three, low micromolar MMP-13 inhibitors as a result of the HTS and crystallographic studies revealing that two molecules of the identified inhibitors are simultaneously bound in two distinct binding sites, one known and a second, previously unknown exosite, a structureguided
drug design approach will be launched. The origin of synthetic considerations is the design of fused inhibitor scaffolds by exploiting the advantages of known MMP-13 inhibitor binding modes.
The synthetic planning represents a fragment-based approach, which allows the modular and fast preparation of a large number of potential drug candidates.
The synthetic studies will be accompanied and clearly rationalized by structural analysis and molecular models and comprehensive in vitro SAR studies will validate the optimization process. The drug design approach elaborated within the proposal is focusing on the improvement of selectivity and
inhibiting potency of the three initially identified MMP-13 inhibitors, in order to ultimately develop efficient anti-osteoarthritic drugs.
StatusFinished
Effective start/end date6/08/1430/09/18