کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9002128 | 1118574 | 2005 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Exploitation of the unusual thermodynamic properties of human myeloperoxidase in inhibitor design
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. It uses hydrogen peroxide and chloride to catalyze the production of hypochlorous acid (HOCl), which contributes to both bacterial killing and oxidative injury of host tissue. Thus, MPO is an interesting target for anti-inflammatory therapy. Here, based on the extraordinary and MPO-specific redox properties of its intermediates compound I and compound II, we present a rational approach in selection and design of reversible inhibitors of HOCl production mediated by MPO. In detail, indole and tryptamine derivatives were investigated for their ability to reduce compounds I and II and to affect the chlorinating activity of MPO. It is shown that these aromatic one-electron donors bound to the hydrophobic pocket at the distal heme cavity and were oxidized efficiently by compound I (k3), which has a one-electron reduction potential of 1.35 V. By contrast, compound II (E°Ⲡof the compound II/ferric couple is 0.97 V) reduction (k4) was extremely slow. As a consequence compound II, which does not participate in the halogenation cycle, accumulated. The extent of chlorinating activity inhibition (IC50) was related to the k3/k4 ratio. The most efficient inhibitors were 5-fluorotryptamine and 5-chlorotryptamine with IC50 of 0.79 μM and 0.73 μM and k3/k4 ratios of 386,000 and 224,000, respectively. The reversible mechanism of inhibition is discussed with respect to the enzymology of MPO and the development of drugs against HOCl-dependent tissue damage.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 69, Issue 8, 15 April 2005, Pages 1149-1157
Journal: Biochemical Pharmacology - Volume 69, Issue 8, 15 April 2005, Pages 1149-1157
نویسندگان
Walter Jantschko, Paul Georg Furtmüller, Martina Zederbauer, Karin Neugschwandtner, Isabella Lehner, Christa Jakopitsch, Jürgen Arnhold, Christian Obinger,