Abstract
The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with β-thalassemia. A sub-library of 64 compounds was screened for matriptase-2 inhibition and several active compounds were identified. (S)-Ethyl 2-(benzyl(3-((4-carbamidoylphenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoacetate ((S)-12) showed an IC50 value of less than 10 µM. Structure-activity relationships were discussed and proposals to design new matriptase-2 inhibitors were made.
Highlights
Thalassemias are among the most common inherited diseases worldwide
The milder form, β-thalassemia intermedia, does not necessitate blood transfusions, and leads to iron overload due to chronic suppression of the hepcidin synthesis caused by ineffective erythropoiesis, thereby leading to increased iron absorption in the duodenum [1,2,3,4]
In other diseases that are correlated with primary iron overload, like HFE-associated hemochromatosis, iron accumulation is hindered by phlebotomy, but this is not possible in the case of β-thalassemia
Summary
Thalassemias are among the most common inherited diseases worldwide. They are classified as anaemia and typified by abnormal formation of hemoglobin [1]. Β-thalassemia, is characterized by a decreased synthesis of β-globin chains or by the complete lack of it, resulting in a severe anaemia and/or red blood cell abnormalities. Patients affected by β-thalassemia major, the most severe form, require chronic red blood cell transfusions As a result, they develop secondary iron overload. It was demonstrated that matriptase-2 acts as a suppressor of the expression of the hepatic hormone hepcidin It probably inactivates the bone morphogenetic protein co-receptor hemojuvelin (m-HJV) by cleaving it into an inactive form [10,15]. The phosphorylation of SMADs (sons of mothers against decapentaplegic homologue) is suppressed and the expression of HAMP, the gene encoding hepcidin, decreases This leads to a higher level of iron in the blood plasma (Figure 1). By taking the primary substrate specificity of matriptase-2 into account, a focused screening approach was used and is described
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