INHIBITION OF NEUTROPHIL SERINE PROTEINASES BY SURAMIN

Suramin, a hexasulfonated naphtylurea recently used as an anti-tumor d rug, is a potent inhibitor of human neutrophil elastase, cathepsin G, and proteinase 3. The complexes it forms with these enzymes are partia lly active on synthetic substrates, but full inhibition takes place wh en elastase activity is measured with fibrous elastin or when cathepsi n G activity is measured using platelet aggregation. One molecule of e lastase binds four molecules of suramin with a K-i of 2 X 10(-7) M as determined by enzyme inhibition or intrinsic fluorescence enhancement of suramin. The binding curves show no sign of cooperativity or antico operativity. The K-i for the complexes with cathepsin G and proteinase 3 are 8 x 10(-8) and 5 x 10(-7) M, respectively. Ionic strength incre ases the K-i of the elastase suramin complex in a way that suggests th at four of the six sulfonate groups of suramin form ionic interactions with basic residues of the enzyme and that at saturation almost all a rginines of elastase form salt bridges with suramin. The neutrophil pr oteinase-inhibitory activity of suramin might be used to prevent tissu e destruction and thrombus formation in diseases where massive infiltr ation and activation of neutrophils take place.