Cysteine proteinase inhibitors and inhibitor precursors

Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 11 to 14 amino acid residues in defined sequence

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530331, 530330, 530329, 530328, C07K 500, C07K 700, A61K 3700

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active

053170865

ABSTRACT:
Compounds are provided that are useful in inhibiting cysteine or serine proteinases. The compounds define a peptide backbone with a sulfur atom substituted in the backbone. A leaving group is associated, or bonded, to a carbon atom adjacent to the sulfur atom. The leaving group is displaceable either by hydrolysis under physiological conditions (with the hydrolyzed compound forming an aldehyde enzyme inhibitor) or by an active-site nucleophile of a cysteine or serine proteinase. When the leaving group is displaced by hydrolysis, then the compound functions as a protected derivative of the aldehyde functional group and is stabilized against oxidation or degradation, yet allows for release of the aldehyde moiety at the pharmacological site of action. The peptide sulfide analogues bearing a leaving group displaced by the active-site nucleophile covalently bond cysteine or serine proteinases and thus irreversibly inhibit these enzymes.

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Rich, "Inhibitors of Cysteine Proteinases", Chpt. 4 in Proteinase Inhibitors, Elsevier Science Publishers (1986).
Shaw et al., "The Specificity of Cathepsin B", Acta Biol. Med. Germ., 40, 1503-1511 (1981).
Smith et al., "Inhibition of Cathepsin B by Peptidyl Aldehydes and Ketones: Slow-Binding Behavior of a Trifluoromethyl Ketone," Biochemistry, 27, 6568-6573 (1988).
MacKenzie et al., ".sup.13 C NMR Study of the Stereospecificity of the Thiohemiacetals Formed on Inhibition of Papain by Specific Enantiomeric Aldehydes", Biochemistry, 25, 2293-2298 (1980).
Westerick et al., "Aldehydes as Inhibitors of Papain," J. of Biol. Chem., 247 (24), 8195-8197 (1972).
Shaw, "Cysteinyl Proteinases and Their Selective Inactivation," Adv. Enzymol. Relat. Areas Mol. Biol., 63, 271-347 (1990).

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