Cysteine proteases inhibition

Sortino et al. reported the use of light irradiation on SAMs supporting the anticancer drug flutamide to study its photoreactivity and product release of nitric oxide. The authors were able to conduct studies in the absence of noxious side effects such as singlet-oxygen photosensitization and observed that nitric oxide production halted when the light was turned off [103], Another photoactive molecule, azobenzene, has recently been exploited in the SAM community to aid in studies on cell adhesion and enzyme inhibition [104], Pearson and coworkers described the use of photoisomerizable SAMs of azobenzene to conduct a series of serine and cysteine protease inhibition experiments. When light of 340-380 nm is used, the... 

More recently, miraziridine A (113) was isolated from a marine sponge related to Theonella mirabilis and shown to inhibit the cysteine protease cathepsin B. It has been shown that the aziridine ring plays a key role in this biological activity and gives rise to irreversible inhibition of cathepsins B and L, presumably through... 

Membrane extracts from adult H. contortus were enriched 24-fold for cysteine protease activity by passage over a Thiol-Sepharose affinity column and the proteins obtained (abbreviated as TSBP) were clearly localized to the microvillar surface of the intestinal cells (Knox et al., 1995,1999). TSBP comprised a prominent 60 kDa protein and several minor bands between 35 and 45 kDa and 97 to 120 kDa (Fig. 13.2). Protease activity at 38, 52 and 70 kDa was attributable to cysteine proteases and at 70 and 88 kDa to serine/metalloproteases, as judged by inhibition analyses. Lectin-binding studies showed that most of the TSBPs were glycosylated. Expression library... 

NO is recognized as a mediator of bone cell metabolism, where it regulates osteoblast and osteoclast activity [141-143]. Osteoporosis, which frequently occurs in postmenopausal women, is a systemic skeletal disease associated with abnormal bone resorption. Addition of NO or NO donors to osteoclasts in vitro results in a reduction in bone resorption, whereas NO synthase inhibitors increase bone resorption, both in vitro and in vivo. Further research has shown that NO reduces bone resorption, via inhibition of the cysteine protease cathepsin K, which is believed to be a key protease in bone resorption. Most of the NO donors, i.e., nitroglycerin, 3-... 

The a-ketoamide group is a well-known electrophile for the inhibition of both serine and cysteine proteases. Introducing a pyrazole as the N-substituent of the ketoamide provides potent inhibitors of Cat K [50]. SAR exploration of the P2-P3 residues in a series of Cat K inhibitors led to the identification of the pyrrolidine... 

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). 

Inhibits serine proteases such as trypsin and chymotrypsin. Also inhibits cysteine proteases (reversible by reduced thiols) and mammalian acetylcholinesterase Inhibits ATPase, alkaline phosphatase and tyrosine phosphatase Reagent for maintaining -SH groups in the reduced state. Effective for reducing protein disulfide bonds prior to SDS-PAGE... 

A novel concept of using bioadhesive polymers as enzyme inhibitors has been developed [97]. Included are derivatives of poly acrylic acid, polycarbophil, and car-bomer to protect therapeutically important proteins and peptides from proteolytic activity of enzymes, endopeptidases (trypsin and a-chymotrypsin), exopeptidases (carboxypeptidases A and B), and microsomal and cytosolic leucine aminopeptidase. However, cysteine protease (pyroglutamyl aminopeptidase) is not inhibited by polycarbophil and carbomer [97]. 

We will synthesize a 6,000-member focused library designed to inhibit the caspase family of cysteine proteases involved in apoptosis. 

At a concentration of 3 pM. 1,4-benzoquinone caused 50% inhibition of CPP32, an interleukin-ip-enzyme/Ced-3 cysteine protease involved in the implementation of apoptosis and which is present in myeloid cells (Hazel et al., 1996). 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

A straightforward approach is to hunt for short polypeptides that meet the specificity requirement of an enzyme but which, because of peculiarities of the sequence, are acted upon very slowly. Such a peptide may contain unusual or chemically modified amino acids. For example, the peptide Thr-Pro-nVal-NMeLeu-Tyr-Thr (nVal=norvaline NMeLeu = N-methylleucine) is a very slow elastase substrate whose binding can be studied by X-ray diffraction and NMR spectroscopy.6 Thiol proteases are inhibited by succinyl-Gln-Val-Val-Ala-Ala-p-nitroanilide, which includes a sequence common to a number of naturally occurring peptide inhibitors called cystatins.f They are found in various animal tissues where they inhibit cysteine proteases. 

The diazomethyl ketone functional group was first observed to be an affinity label by Buchanan and co-workers who showed that the antibiotic azaserine, an O-diazoacetyl derivative, 9 inhibited an enzyme in the biosynthesis of purine by alkylation of a cysteine residue. 10 The acid protease pepsin was then observed to be inhibited by peptidyl diazomethyl ketones in the presence of copper ions with the resulting esterification of an aspartate residue. 11 Two peptidyl diazomethyl ketones, Z-Phe-CHN2 and Z-Phe-Phe-CHN2, were found to irreversibly inactivate papain, a cysteine protease. 12 Since these reports, many peptidyl diazomethyl ketones have been prepared primarily as inhibitors of various cysteine proteases. 7 Peptidyl diazomethyl ketones are also synthetic intermediates and have been used to prepare chloromethyl ketones (Section 15.1.3), 13 bromomethyl ketones (Section 15.1.3), acyloxymethyl ketones, 14 and (i-peptides. 15 A few peptidyl diazoalkyl ketones have been reported. 16,17 ... 

Peptide nitriles are reversible inhibitors of cysteine proteases. 1,2 Peptide nitrile reacts with the active site thiol group to form an imidothioate, a dead-end product that does not undergo hydrolysis to an amide.134 This imidothioate derivative has been detected by NMR spectroscopic studies.P 5 The inhibition of papain, a cysteine protease, by a peptide nitrile proved to be reversible in a dialysis experiment. 3 Peptide nitriles are weaker inhibitors of cysteine proteases than the corresponding aldehydes. 61 Most peptide nitriles show poor inhibition toward serine proteases, however those nitriles with proper peptide sequences are potent inhibitors of serine proteases. 7-9 ... 

Recently discovered antitumor monocyclic and bicyclic (3-lactam systems [40-42] are, in general, in good agreement with the phenomenon of azetidin-2-one pharmacophore of inexhaustible pharmacological potential on account of the specific ability of its numerous derivatives to inhibit not only bacterial transpeptidase, but also mammalian serin and cystein proteases [43]. As a measure of cytotoxicity, some compounds have been assayed against nine human cancer cell lines. 

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