Exploitation of the unusual thermodynamic properties of human myeloperoxidase in inhibitor design

Abstract

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 ( k 3), which has a one-electron reduction potential of 1.35 V. By contrast, compound II ( E°′ of the compound II/ferric couple is 0.97 V) reduction ( k 4) was extremely slow. As a consequence compound II, which does not participate in the halogenation cycle, accumulated. The extent of chlorinating activity inhibition (IC 50) was related to the k 3/ k 4 ratio. The most efficient inhibitors were 5-fluorotryptamine and 5-chlorotryptamine with IC 50 of 0.79 μM and 0.73 μM and k 3/ k 4 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.