A. Sahu et Mk. Pangburn, INVESTIGATION OF MECHANISM-BASED INHIBITORS OF COMPLEMENT TARGETING THE ACTIVATED THIOESTER OF HUMAN C3, Biochemical pharmacology, 51(6), 1996, pp. 797-804
An intramolecular thioester bond in complement protein C3 is vital for
covalent attachment of C3b (the proteolytically activated form of C3)
to biological surfaces and for activation of the complement system. P
roteolytic removal of C3a from C3 activates the thioester in the C3b f
ragment. Activated C3b primarily forms ester bonds with hydroxyl group
s of carbohydrates on complement activating surfaces, but it has also
been shown to react with the hydroxyl group of tyrosine and with speci
fic Ser and Thr residues on IgG and on complement protein C4b. To exam
ine the reactivity of the thioester, several families of hydroxylated
compounds were examined. Reactivity of a series of substituted phenols
varied over two orders of magnitude and demonstrated a linear correla
tion between reactivity and the Hammett substituent constants. Hydroxy
lated drugs including members of the L-DOPA/epinephrine family and hyd
roxamic acids also were examined. Compounds were identified that were
20,000 times more reactive than carbohydrates. These compounds were fo
und to inhibit both the classical and alternative pathways of compleme
nt activation. Although the specificity of the thioester for its natur
al biological targets appears to be determined by many structural feat
ures, the data presented here demonstrate that increasing the nucleoph
ilic character of the target hydroxyl group can increase the potency o
f a synthetic inhibitor many orders of magnitude.