Search results for "oteinase inhibitor"
showing 10 items of 86 documents
Hamster Bcl-2 Protein Is Cleaved in Vitro and in Cells by Caspase-9 and Caspase-3
2001
Full-length cDNA of hamster bcl-2 (771 nt) was cloned by RT-PCR and inserted into pGEX-4T-1 to produce the recombinant hamster Bcl-2 protein. The purified recombinant Bcl-2 protein (26.4 kDa) was used as a substrate for the active human caspase-3 and caspase-9 in vitro. It is shown here that Bcl-2 is efficiently cleaved by caspase-3 to a 23 kDa fragment. Although not possessing a putative caspase-9 cleavage site in its sequence, hamster Bcl-2 was also cleaved by caspase-9 into exactly the same 23 kDa cleavage product, indicating that cleavage occurred at the same site. Caspase-3- and caspase-9-mediated cleavage of Bcl-2 was efficiently blocked by caspase-3 (zDEVD) and caspase-9 (zLEHD) inhi…
Possible regulatory mechanisms responsible for the high expression of serpin protease inhibitor PI-9 in ER+ -derived breast cancer stem cells.
2015
Breast cancer (BC) is the most common endocrine cancer and the second leading cause of cancer-related death in women. About 75% of BCs expresses high levels of estrogen receptors that sustain the tumor growth. Moreover, in BC estrogens prevent apoptosis induced by granzyme B released by cytotoxic T lymphocytes and NK cells through the production of the granzyme B inhibitor PI-9. As a consequence, cancer cells acquire the ability to escape immune surveillance’s signaling. Although some studies explored the role of PI-9 in BC cells, its presence has not been investigated in cancer stem cells so far. In this research, tertiary tumorspheres were obtained from estrogen receptor-alfa positive (ER…
Identification of a silicatein(-related) protease in the giant spicules of the deep-sea hexactinellid Monorhaphis chuni.
2008
SUMMARYSilicateins, members of the cathepsin L family, are enzymes that have been shown to be involved in the biosynthesis/condensation of biosilica in spicules from Demospongiae (phylum Porifera), e.g. Tethya aurantium and Suberites domuncula. The class Hexactinellida also forms spicules from this inorganic material. This class of sponges includes species that form the largest biogenic silica structures on earth. The giant basal spicules from the hexactinellids Monorhaphis chuni and Monorhaphis intermedia can reach lengths of up to 3 m and diameters of 10 mm. The giant spicules as well as the tauactines consist of a biosilica shell that surrounds the axial canal, which harbours the axial f…
Multipolar interactions in the D pocket of thrombin: large differences between tricyclic imide and lactam inhibitors.
2006
Two series of tricyclic inhibitors of the serine protease thrombin, imides (+/-)-1-(+/-)-8 and lactams (+/-)-9-(+/-)-13, were analysed to evaluate contributions of orthogonal multipolar interactions with the backbone C=O moiety of Asn98 to the free enthalpy of protein-ligand complexation. The lactam derivatives are much more potent and more selective inhibitors (K(i) values between 0.065 and 0.005 microM, selectivity for thrombin over trypsin between 361- and 1609-fold) than the imide compounds (Ki values between 0.057 and 23.7 microM, selectivity for thrombin over trypsin between 3- and 67-fold). The increase in potency and selectivity is explained by the favorable occupancy of the P-pocke…
Proteasome comprising a beta1 inducible subunit acts as a negative regulator of NADPH oxidase during elicitation of plant defense reactions.
2005
Elicitation of defense reactions in tobacco by cryptogein, triggered a production of active oxygen species (AOS) via the NADPH oxidase, NtrbohD, and an accumulation of beta1din, a defense induced beta-type subunit of 20S proteasome. The proteasome inhibitor, MG132, stimulated this AOS production. Tobacco cells transformed with sense constructs of beta1din showed an inhibition of the AOS production following elicitin treatment, whereas the antisense transformed cells showed a strongly enhanced AOS production. In cells transformed with sense construct of beta1din, the NtrbohD transcripts failed to be induced by cryptogein as observed in control and antisense transformed cells. Conversely, in …
Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.
2020
Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversibl…
Synthesis and biological evaluation of papain-family cathepsin L-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antipr…
2014
Novel papain-family cathepsin L-like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure-activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzod…
Amino Acid derivatives as new zinc binding groups for the design of selective matrix metalloproteinase inhibitors.
2012
A number of matrix metalloproteinases (MMPs) are important medicinal targets for conditions ranging from rheumatoid arthritis to cardiomyopathy, periodontal disease, liver cirrhosis, multiple sclerosis, and cancer invasion and metastasis, where they showed to have a dual role, inhibiting or promoting important processes involved in the pathology. MMPs contain a zinc (II) ion in the protein active site. Small-molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In an effort to devise new approaches to selective inhibitors, in this paper, we describe the synthesis and preliminary biological evaluation of amino acid derivatives as new zinc b…
Cathepsin L in Normal and Pathological Bone Remodeling
2011
Abstract Cathepsin L is a ubiquitous lysosomal cysteine endopeptidase that is mainly involved in the metabolic turnover of intracellular proteins. However, it is now well established that this enzyme may also be implicated in the regulation of other important biological processes includ- ing bone resorption. Therefore, altered expression levels of Cathepsin L may result in disturbances of bone homeo- stasis and, eventually, in the onset of pathological condi- tions associated with altered bone turnover. These observations support the concept that Cathepsin L may be regarded as an additional target for the development of novel therapeutic options for the treatment of patients with bone disea…
Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases.
2008
The receptor for advanced glycation end products (RAGE) is a 55-kDa type I membrane glycoprotein of the immunoglobulin superfamily. Ligand-induced up-regulation of RAGE is involved in various pathophysiological processes, including late diabetic complications and Alzheimer disease. Application of recombinant soluble RAGE has been shown to block RAGE-mediated pathophysiological conditions. After expression of full-length RAGE in HEK cells we identified a 48-kDa soluble RAGE form (sRAGE) in the culture medium. This variant of RAGE is smaller than a 51-kDa soluble version derived from alternative splicing. The release of sRAGE can be induced by the phorbol ester PMA and the calcium ionophore c…