Project Summary
Matrix metalloproteinases (MMPs) play an important role in tissue remodeling associated
with various physiological and pathological processes such as morphogenesis, angiogenesis
, tissue repair, arthritis, chronic heart failure, chronic obstructive pulmonary disease,
chronic inflammation, and cancer metastasis. As a result, MMPs are considered as viable
drug targets in the therapy of the above diseases. In spite of the high therapeutic
potential of MMP inhibitors, all clinical trials except for doxycycline for periodontal
diseases have failed so far. This can be attributed to 1. poor selectivity of the MMP
inhibitors, 2. poor target validation for the targeted therapy, as well as 3. poorly
defined predictive preclinical animal models for safety and efficacy. Lessons from
previous failures and recent discoveries of oxidative/nitrosative activation and
phosphorylation of MMPs, non-matrix related intra- and extracellular targets of MMP
give new hope for MMP inhibitor development for both chronic and acute diseases.
Activation of MMP-2 plays an important role in cardiac ischemic injury and in the mechanism
of cardiac stress adaptation. We have previously shown that in hyperlipidemic animals, which
represent a high-risk group for ischemic heart disease, the adaptive response of the heart
is diminished possibly due to a pathological activation of MMPs via nitric oxide - peroxynitrite-induced
oxidative/nitrosative stress. Therefore, the aim of MMPharma consortium is to develop selective
MMP inhibitors capable of reducing infarct size as a new therapeutic option against acute
myocardial infarction. The consortium is based on a co-operation of 4 biotechnology
companies, a technology transfer office and academic research groups using the most
advanced technologies in chemoinformatics, bioinformatics, genomics, and toxicogenomics.
MMPharma consortium is capable of executing a fast-reacting integrated preclinical
drug-development process from target identification via generation of innovative molecular
libraries and development of supporting biomedical instruments to pharmacological testing
in complex animal models as well as in human clinical trials.
