Screening And Characterization Of Matrix Metalloproteinase Inhibitors From Natural Products

Matrix metalloproteinases (MMPs) are a family of zinc dependent enzymes thatcan degrade components of the extracellular matrix (ECM) and basementmembranes. MMPs can degrade ECM components, other proteases, clottingfactors, chemotactic molecules, latent growth factors, growth-factor bindingproteins, adhesion molecules, cell surface receptors etc. MMPs play roles inmany important physiological and pathological functions, includingreproduction, angiogenesis, development, morphogenesis, tissue remodeling,arthritis, cardiovascular diseases, stroke, Alzheimer's disease, multiple sclerosis,neurological diseases, allergy and cancer progression and metastasis. As MMPsinvolve in many pathological conditions, many MMP inhibitors (MMPIs) havebeen developed with the aim of interfering and treating diseases. ADAMs aremembrane-anchored metalloproteases that process and shed the ectodomains ofmembrane-anchored growth factors, cytokines and receptors. Members ofADAM-TS may be distinguished from the ADAM family members based onthe multiple copies of thrombospondin 1-like repeats they carry. ADAMs andADAM-TS also have essential roles in fertilization, angiogenesis, neurogenesis,heart development and cancer. They share the similar sequence HEXXH withMMPs in their catalytic domain. Therefore, some MMPI may be also theinhibitor of ADAMs and ADAM-TS.We intended to screen MMPI from natural products and Chinese traditionalmedicine. Many natural products such as polyphenols and flavanoids have beenreported anti-inflammatory, anti-tumor, and antioxidant. In our research, wehave found a new class of inhibitors of MMP-1, -2, -3, -7, -9, -14, -16, -17 and-26 which used fluorescent assays in vitro. To study the mechanism of theinhibition, we used compound 1 and MMP-2, MMP-9 in the enzyme kineticsanalysis. The results show the inhibition is mainly competitive orpredominantly competitive. These new class chemicals also showed inhibitionto ADAM-10 and -17.Flavonoids, polyphenols have been reported for therapeutic benefit for anumber of diseases including cardiovascular diseases, cancer, inflammation, etal. They may exert their anti-cancer and anti-inflammation activities throughmultiple targets. We will continue to test these chemicals on MMP inhibition,biological activities and preclinical assays. Our research will accelerate pace offinding and synthesizing new MMPI, and interpret the molecular mechanism ofsome Chinese traditional medicine.