Protease Inhibitors

Although necessary for proper function during inflammation and remodeling, proteases can cause serious tissue damage if improperly regulated. Below are important protease inhibitors which are important in keeping proteases in check.

Secretory leukocyte protease inhibitor (SLPI): is a highly cationic single-chain protein with eight intramolecule disulfide bonds. It is found in large quantities in bronchial, cervical and ansal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase and mast cell chymase. The gene for SLPI is expressed by cells at many mucosal surfaces. Many diseases such as emphysema, cystic fibrosis and idiopathic pulmonary fibrosis are characterized by increased levels of neutrophil elastase, and SLPI is one of the major defenses against the destruction of pulmonary tissues and epithelial tissues by neutrophil elastase.

SLPI as well as possibly mucins, nonspecific antiviral molecules and HIV-1specific IgA and IgG may control HIV-1 infectivity in the oral cavity and explain the rarity of oral transmission of HIV-1 by saliva (Wahl, Amer. J. Pathol., 150(4) 1997). Increased levels of SLPI in saliva and plasma may be an indicator of HIV infection. Increased levels of SLPI in nasal secretions and bronchoalveolar fluids may also be an indicator of inflammatory lung conditions or allergic reactions and increased levels of SLPI in plasma may be indicative of pneumonia.

The antiviral activity of SLPI against HIV is due to the interference of SLPI in events that are mediated by protease, such as entry into the host cell and replication of viral genetic material.

Cysteine proteinase Inhibitors

Small Molecule (peptide or peptidomimetics) Inhibitors:

(1) Small molecule inhibitors of Cathepsins:

Small molecules whcih inhibit catehpsins are known. Some small molecule inhibitors may have higher seletivity toward a particular form of cathepsin than other forms of cathepsin, or may only inhiibt one form of cathepsin. For example, small molecules that inhibit cathepsin L activity in the treatment of certain indications are known. (Yong, US 2004/0009891A1, ¶169).

–E-64 (trans-epoxy-succiynl-L-leucylamido-(4-guanidino)butane: is a specific and irreversible inhibitor of cysteine proteinases. It has been shown to reduce proteinuria in an animal model of anti-GBM antibody disease (Baricos, Archives of Bioch. and Biophy. 288(2), 1991, pp. 468-472; see also Baricos (Bioch. and Biophy. Research Communcations, 155(3), 1988, pp. 1318-1323).

–Ep475 (trans-epoxysuccinyl-L-leucylamido-(3-methyl)butane): is a specific inhibitor of cysteine proteinases, including cathepsins B and L and has been shown to reduce proteinuria in a neutrophil-independent model of human anti-GBM antibody diasease, a well characterized model of human glomerulonephritis . (Baricos, Archives of Bioch. and Biophy. 288(2), 1991, pp. 468-472)

Z-Phe-Ty(O-t-butyl)CHN2: is a specific, irreversible cysteine proteinase inhibitor with a high degree of selectivity toward cathepsin L. (Baricos, Archives of Bioch. and Biophy. 288(2), 1991, pp. 468-472)