Ischemic heart disease developing as a consequence of hyperlipidemia results in heart failure, arrhythmias, and myocardial infarction, which are leading causes of morbidity and mortality in the European Union. The heart is able to adapt to ischemic stress via a yet unclear mechanism which results in a dramatic decrease in ischemic damage (infarct volume) (see reviews: 1; 13; 14). The exploration of the cellular mechanisms of stress adaptation may lead to the development of new, highly effective cardioprotective drugs capable of reducing infarct size.
Matrix metalloproteinases (MMPs, collagenases, gelatinases) are members of the zinc-dependent multidomain endopeptidases (Fig 1.1.). MMPs play a role not only in degradation of the extracellular matrix, but also in acute regulatory processes (vessel tone, platelet aggregation, activation of vasomotor peptides, etc.). Proteolytic activity of the MMPs is regulated by their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMP). Imbalances between MMPs and TIMPs are involved in the pathological mechanisms of numerous diseases including acute ischemic injury, infarction, systemic inflammatory response syndrome (SIRS), and other non-cardiovascular diseases such as obstructive pulmonary diseases, skin aging, or cancer metastasis (3; 20; 28; 30; 33). The novel discovery of acute activation of MMPs in the heart opened new perspectives in cardiovascular research in the last couple of years. Recently, a new way of acute activation of MMPs has been discovered. Reactive oxygen species (e.g. peroxynitrite, which is synthesized from superoxide-anions and NO) activate MMPs, a mechanism that plays an important role in ischemic tissue injury (21; 34) (Fig 1.2.). Our very recent findings prove that stress adaptation attenuates the level of peroxynitrite and the activation of MMPs in cardiac muscle (5; 13; 19). Moreover, certain MMP-inhibitors decrease infarct size in ex vivo experiments (15) that is defended by consortium leader institution by patent application (No.P0500692 Hungarian patent application: use of MMP inhibitors in the preparation of pharmaceutical compositions of cardioprotective effect, date of application: 07. 15. 2005). We have shown previously that the development of endogenous ischemic tolerance is impaired in hyperlipidemic animals, corresponding to patients with high-risk of ischemic heart disease. Although the complete mechanism of hyperlipidemia- induced deterioration of ischemic tolerance is unclear, we have explored several details of this phenomenon. Our preliminary data show that pathological oxidative activation of MMPs is also involved in this mechanism (11; 14). Numerous pharmaceutical companies (e.g. Bayer) made unsuccessful efforts to develop new MMP inhibitors due to safety problems. These safety problems can be attributed to the lack of MMP isoenzyme selectivity of the lead molecules, i.e. probably the inhibition of MMP-1, which was not known at the time. Therefore, development of selective MMP-2, MMP-9, or MMP-13 inhibitors, which have no effect on MMP-1 activity, may result in tissue-protective lead molecules that have improved safety parameters. Besides cardiovascular diseases (infarction, cardiomyopathies, heart failure), several other conditions, e.g. gastroprotection or cancer metastasis could also be targeted by selective MMP inhibitor molecules (2; 3; 29; 29).
One of the major goals of the present project is to improve and accelerate the development of MMP inhibitors using a novel chemogenomic approach, sequence homology based drug-design, which extends the conventional chemo- and bioinfomatics tools. The concept of organizing drug targets into related gene families is one of the major directions of chemogenomics, since sequence similarity could enable rapid identification of the function of related proteins. One small molecule inhibitor identified in a family can help to discover inhibitors to other proteins within the same gene-family, provided that we understand the structural consequences of the different amino acid compositions around the binding site. That information can be exploited in the design of selective inhibitors, which can be obtained by subtle structural modifications of robust, non-selective agents. Furthermore, structural analysis of the previously identified selective inhibitors can identify unique structural changes which - if placed into different structural scaffolds - lead to a transition of the selectivity from one isoform to another (“selectivity jumping”, see Fig 1.3). According to the present trend, this target-family based drug research could become a standard discovery paradigm in the post-genomic era, when huge amounts of information is available about the targets, their amino acid sequences and their relationships.
