Cysteine peptidase inhibitors

Cystatin refers to a diverse family of protein cysteine protease inhibitors. There are three general types of cystatins Type 1 (stefens), which are primarily found in the cytoplasm but can appear in extracellular fluids Type 2, which are secreted and found in most extracellular fluids and Type 3, which are multidomain protease inhibitors containing carbohydrates and that include the kininogens. Cystatin 3 is used to measure renal function in clinical chemistry. See Barrett, A.J., The cystatins a diverse superfamily of cysteine peptidase inhibitors, Biomed. Biochim. Acta 45,1363-1374,1986 Katunuma, N., Mechanisms and regulation of lysosomal proteolysis, Revis. Biol. Cellular 20, 35-61, 1989 Gauthier, F., Lalmanach, G., Moeau, T. et al., Cystatin mimicry by synthetic peptides, Biol Chem. Hoppe Seyler 373, 465-470, 1992 Bobek, L.A. and Levine,... 

Cystatins, a human superfamily of cysteine peptidase inhibitors. They are tight-binding reversible inhibitors of many cysteine proteases, and are not capable of inhibiting other proteases. Members of this superfamily contain at least two intrachain disulfide bonds and an a-helical structure over a distance of about 100 aa. This superfamily comprises (i) Family 1 (intracellular cystatins) cystatin A and cystatin B (ii) Family 2 (extracellular and/or transcellular cystatins) cystatin G, cystatin D, cystatin E, cystatin F, cystatin G, cystatin S, cystatin SA and cystatin SN and (iii) Family 3 (intravascular cystatins) LMW-kininogen and HMW-kininogen [A. J. Barret, Trends Biol. Sci. 1987, 12, 193 S. Nagpal et al., J. Invest. Dermatol. 1997, 109, 91 M. Zanatti,... 

The action of a peptidase can be neutralized by an inhibitor. Some inhibitors are very broad in their action and are capable of inhibiting many different peptidases, including peptidases of different catalytic types. Some inhibitors are assumed to be specific for a particular catalytic type, but can inhibit peptidases of different types. Leupeptin, for example, is widely used as an inhibitor of serine peptidases from family SI, but it is also known to inhibit cysteine peptidases from family Cl. Cysteine pqrtidase inhibitors such as iodoacetic acid interact with the thiol of the catalytic cysteine. However, this reduction can occur on any thiol group and can affect other, predominantly intracellular, peptidases with a thiol dependency. One example is thimet oligopepti-dase. Metal chelators such as EDTA can inhibit meta-llopeptidases, but can also affect peptidases that have a requirement for metal ions that is indq>endent of their catalytic activity, such as the calcium-dependent cysteine endopqrtidase calpain 1. 

Inhibitors which interact only with peptidases of one catalytic type include pepstatin (aspartic peptidases) E64 (cysteine peptidases from clan CA) diisopropyl fluorophosphates (DFP) and phenylmethane sulfonyl-fluoride (PMSF) (serine peptidases). Bestatin is a useful inhibitor of aminopeptidases. 

Cat B is an abundant and ubiquitously expressed cysteine peptidase of the papain family and makes up a major fraction of lysosomal enzymes that is capable of degrading components of the extracellular matrix in various diseases [30-32]. Cat B is also a prognostic marker for several types of cancer [33], and increased expression and secretion of cat B has been shown to be involved in the migration and invasion of various tumours [34—36], The precise role of cat B in solid tumours is not fully understood, but it has been proposed to participate, along with other cysteine cathepsins, in metastasis, angiogenesis, and tumour progression [37], Indeed, cat B inhibitors reduce both tumour cell motility and invasiveness in vitro [38], Recently, metal complexes based on rhenium, gold and palladium were shown to be effective inhibitors of cat B [39-44],... 

The structures of hepatitis A viral 3C proteinases complexed with tetrapeptidyl-based methyl ketone inhibitors were shown to have an episulfide cation embedded in them. The authors concluded that the mechanism of inactivation of 3G peptidases by methyl ketone inhibitors is different than those operating in serine proteinases or in papain-like cysteine peptidases <2006MI673>. 

Various peptide Michael acceptors have been described as a new class of inactivators for cysteine proteases. 5-7 The carbonyl group of the scissile peptide bond in the substrate is replaced by a nucleophile trapping moiety such as a vinylogous structure. An amino acid vinyl sulfone, l-(methylsulfonyl)-4-phenylbut-l-en-3-amine [H2NCH(Bzl)CH=CHS02Me] and a dipeptide derivative, Gly-HNCH(Bzl)CH=CHS02Me have both been prepared as inhibitors of cysteine proteases, leucine aminopeptidase and dipeptidyl peptidase I, respectively.1 5 A series of peptide vinyl sulfones has been synthesized as potent inhibitors for different cysteine proteases. 1A8 ... 

In addition to being an inhibitor of papain-like cysteine proteases, cystatin C has recently been shown be an efficient inhibitor of some of the cysteine proteases of another family of cysteine proteases, called the peptidase family C13, with human legumain as a typical enzyme (C6). Human legumain has, like cathepsin S, been proposed to be involved in the class n MHC presentation of antigens (M3). It has also been shown that the cystatin C inhibitory site for mammalian legumain does not overlap with the cystatin C inhibitory site for papain-like cysteine proteases (Fig. 1) and that the same cystatin C molecule therefore is able to simultaneously inhibit one cysteine protease of each type (A 10). 

MEROPS identifies Kunitz-type inhibitors as families 12 and 13, yet they seem to have developed separately in evolutionary history. Families 12 and 13 are referred to as Kunitz-A and Kunitz-P for their origin from animals and plants, respectively. Aprotinin, also known as bovine pancreatic trypsin inhibitor, was one of the first protease inhibitors identified and isolated by Kraut and coworkers in 1930. The 12 family is considerably more homogenous and thought to inhibit only S1 peptidases. In contrast, the 13 family is split into two phylogenetic groups, 13A and 13B, both of which typically inhibit SI peptidases, yet members of the I3A family can also potentially inhibit the A1 family aspartyl proteases and the Cl family cysteine proteases. The first structure of an 13 inhibitor was the... 

LTD, to corresponding E leukotrienes [114,130,221], This enzyme has been partially purified from kidney [130], human plasma [128], RBL cells, guinea pig lung, and guinea pig peritoneal eosinophils [104], In the latter preparations, the peptidase activity could be resolved from the arylsulfatase activity [104], which had earlier been suggested to be responsible for inactivation of SRS [101,102], Inhibitors of the dipeptidase, more potent than L-cysteine, are 3-mercaptopropionic acid and D-peni-cillamine [114],... 

Chicken egg cystatin C consists of one peptide chain with a ca. 120 amino acid residues (Mr 12,700). The two isomers known differ in their isoelectric point (pi 5.6 and pi 6.5) and their immunological properties. This inhibitor inhibits cysteine endopeptidases such as ficin and papain. In fact, cathepsins B, H, and L and dipeptidyl peptidase I are also inhibited. 

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