Preventing Protein Oxidation with Sugars: Scavenging of Hypohalous Acids by 5‑Selenopyranose and 4‑Selenofuranose Derivatives

Heme peroxidases including myeloperoxidase (MPO) are
released at
sites of inflammation by activated leukocytes. MPO generates hypohalous
acids (HOX, X = Cl, Br, SCN) from H2O2; these
oxidants are bactericidal and are key components of the inflammatory
response. However, excessive, misplaced or mistimed production can
result in host tissue damage, with this implicated in multiple inflammatory
diseases. We report here methods for the conversion of simple monosaccharide
sugars into selenium- and sulfur-containing species that may act as
potent water-soluble scavengers of HOX. Competition kinetic studies
show that the seleno species react with HOCl with rate constants in
the range 0.8–1.0 × 108 M–1 s–1, only marginally slower than those for the
most susceptible biological targets including the endogenous antioxidant,
glutathione. The rate constants for the corresponding sulfur-sugars
are considerably slower (1.4–1.9 × 106 M–1 s–1). Rate constants for reaction
of the seleno-sugars with HOBr are ∼8 times lower than those
for HOCl (1.0–1.5 × 107 M–1 s–1). These values show little variation with
differing sugar structures. Reaction with HOSCN is slower (∼102 M–1 s–1). The seleno-sugars
decreased the extent of HOCl-mediated oxidation of Met, His, Trp,
Lys, and Tyr residues, and 3-chlorotyrosine formation, on both isolated
bovine serum albumin and human plasma proteins, at concentrations
as low as 50 μM. These studies demonstrate that novel selenium
(and to a lesser extent, sulfur) derivatives of monosaccharides could
be potent modulators of peroxidase-mediated damage at sites of acute
and chronic inflammation, and in multiple human pathologies.