Cysteine proteases inhibitors

In the rosary pea Abrus precatorius L. Trigollenine as well as its gallic acid ester Precatorine (209) is found (71P195) (Scheme 69). 1-Carboxymethyl-nicotinic acid (210) was isolated as a colorless solid from the marine sponge Anthosigmella cf. raromicrosclera as a cysteine protease inhibitor (98JNP671). This compound was first synthesized in 1991. The sodium... 

Desai PV, Patny A, Sabnis Y, Tekwani B, Gut J, Rosenthal P, Srivastava A, Avery M. Identification of novel parasitic cysteine protease inhibitors using virtual screening. 1. The ChemBridge database. / Med Chem 2004 47 6609-15. 

The N-terminal sequence of one peptide from the 35 kDa zone of H-gal-GP showed some homology to cathepsin B-like cysteine proteases. Molecular cloning has also identified a thrombospondin homologue associated with the diffusely staining region between zones A and B, a galectin associated with zone D (Newlands et al., 1999) and a low molecular weight (approximately 13 kDa) cysteine protease inhibitor, cystatin. 

Zhang, Y., Hsieh, Y., Izumi, T., Lin, E. T., Benet, L. Z., EfFects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats, J. Pharmacol. 

Diaryl-5-anilino-l,2,4-thiadiazoles are found to be potent and selective melanocortin-4-receptor (MC4) agonists for potential use for nerve regeneration and drug addiction <2003BMG185>. Compounds like 56 are being developed as cysteine protease inhibitors (see also Section 5.07.10) <2005JOC6230>. 

By focusing the entire compound collection on the pTyr-pyridone scaffold, the researcher made use of a privileged structural element, since the pyridone was repeatedly utilized to induce /3 strand conformations in serine and cysteine protease inhibitors [157,158]. From this point of view, the potential of a modu-... 

The most convenient way of categorizing the classes of cathepsin inhibitors is based on the nature of the electrophilic warhead that interacts with the sulfhydryl group of the active site cysteine residue. Since a large portion of the binding energy of a cysteine protease inhibitor comes from the covalent interaction with this thiol, the properties of the resulting molecules are largely derived from the electrophile. In broad terms, these inhibitors can be broken down into ketone and nitrile-based reversible covalent inhibitors, or the more recent non-covalent inhibitors based on an aminoaniline template. 

We have also developed targeted library approaches towards cysteine proteases, which are important pharmaceutical targets due to their role in the pathogenesis of many diseases.1251 A common feature of virtually all cysteine protease inhibitors is an electrophilic functionality, such as a carbonyl or a Michael acceptor, which can react with the nucleophilic active site cysteine residue. We specifi-... 

Scheme 7. Synthesis strategy for ketone-based cysteine protease inhibitors.

A. Lee, L. Huang, J. A. Ellman, General Solid-Phase Method for the Preparation of Mechanism-Based Cysteine Protease Inhibitors , J. Am. Chem. Soc 1999, 121, 9907-9914. 

Inverse Relationship between Protease Inhibitors and Metastatic Ability. All proteases, apart from possibly CD, appear to be controlled by endogenous inhibitors. In theory, therefore, the ability of malignant cells to produce metastasis could depend not only on the levels of the specific protease, but also on the concentration of relevant endogenous inhibitors. Thus, the presence of high levels of protease inhibitors might inhibit metastasis, while low levels of inhibitors might enhance metastasis. An inverse relationship between a number of specific inhibitors and metastatic potential has now been shown. Some examples of this type of relationship include TIMP-1 in Swiss 3T3 cells (K4), cysteine protease inhibitors in mouse melanoma cells (R6), and an alpha-1-proteinase inhibitor in rat mammary carcinomas (N2). Furthermore, a newly described serine protease inhibitor, known as maspin, was found to be expressed less frequently in advanced human breast cancers compared with early cancers (Z2). 

Based on their sequence homology, disulfide connectivity, and cysteine location within the sequence and chemistry of the reactive site. Pis can be assigned to distinct families, as classified by Laskowski and Kato. Kunitz-type, Bowman—Birk-type, Potato type I and type II, and squash inhibitors are members of these families shown in Table 3. For inhibitors not falling into these classifications more families have been proposed. Pis can also be classified by their target/mode of action. Plants have been found to express Pis that target serine proteinases, cysteine proteinases, aspartic proteinases, and metallo-proteinases. Serine and cysteine protease inhibitors are the best-studied PIs. ... 

Stefin or cystatin (cysteine protease inhibitor) Homo sapiens 95 (dimer form) 358-363... 

Recently, a series of 4-substituted-3-Cbz-phenyl-(5-lactams (Fig. 37) has been identified as a novel class of cysteine protease inhibitors [364]. 

Wasilewski, M.M., Lim, K.C., Phillips, J. and McKerrow, J.H. (1996) Cysteine protease inhibitors block schistosome haemoglobin degradation in vitro and decrease worm burden and egg production in vivo. Molecular and Biochemical Parasitology 81, 1 79-1 89. 

An azepanone-based inhibitor, 179, of the cysteine protease inhibitor, cathepsin K, was prepared via an asymmetric synthesis from 171 and 172 (Xc = a 4(.V)-benzyloxazolidin-2-one moiety) with ring-closing metathesis of 173 then being used to complete the seven-membered ring in the intermediate 174 with a very high de (Scheme 23). Further functional group manipulations via 175-178 then resulted in 179 <2005TL2799>. 

Doh-ura K., Iwaki T., and Caughey B. (2000). Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J. Virol. 74 4894 1897. 

A distinctive feature of calpain-3 is the propensity to autolysis the half life of the protein in vitro is less than 30 minutes. Autoproteolysis is prevented by replacing the cys residue of the catalytic site with a ser, but is not affected by cysteine protease inhibitors such as calpastatin, E64 and Leupeptin (Sorimachi et al., 1993). The autocatalytic activity and the absence of effective inhibitors have made the... 

Peptide mimetics containing the a-ketoamide moiety are very important because they act as cysteine protease inhibitors. In fact, the a-ketoamide residue forms hemithioacetals with the -SH group of the cysteine residue of the enzyme [32], Nakamura et al. [26b] reported the preparation of a 100-member combinatorial library of a-ketoamides by means of a two-step one-pot synthesis. The first step consisted of the Ugi-4CR between (+/— )lactic acid, amines, isocyanides, and aldehydes leading to the formation of the lactamides 40 which were oxidized to the corresponding pyruvamides 41. This one-pot procedure was performed in THF since the PDC oxidation was incompatible with the presence of methanol. Five a-ketoamides showed an 80% average purity (Scheme 2.17). 

Boc-Tyr-Gly-NHO-Bz, a representative of a novel class of cysteine protease inhibitors, when coadministered with dynorphin A or dynorphin B, significandy prolong antinociception induced by i.t. injection of these dynorphins in the mouse formalin and capsaicin tests (Tan-No et al., 1996, 2005a). This observation indicates that cysteine proteases may be important for terminating dynorphin A- and dynorphin B-induced antinociception. 

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