Neuropeptide Inactivation By Peptidases
Gerard O’Cuinn in Metabolism of Brain Peptides, 2020
For many years it has been assumed that angiotensin II was the peptide which mediated the central control of cardiovascular function and body water balance. Several lines of evidence have indicated that angiotensin III (des - Asp1-angiotensin II) may be the more potent agent in some systems. Studies on angiotensin II and angiotensin III binding in rabbit brain revealed a far greater binding capacity for the latter peptide217. When the effect of adding either bestatin or amastatin along with iontophoretically applied angiotensin II and angiotensin III to cells of the paraventricular and lateral septal nuclei of rats was monitored, it was found that amastatin, an inhibitor of aminopeptidase A and other aminopeptidases, blocked the action of angiotensin II but not of angiotensin III133. This finding appears to support the notion that aminopeptidase A is necessary to effect conversion of angiotensin II to angiotensin III by removal of N-terminal Asp before activity is recorded. Moreover bestatin, an inhibitor of many aminopeptidases brought about an enhancement of the activity of both angiotensin II and angiotensin III. Since it is possible that bestatin inhibits angiotensin A as well as angiotensin III degrading aminopeptidases the possibility that some activity may reside in angiotensin II must be considered.
Tonic Influences on Baroreceptor Reflex Sensitivity By Endogenous Neurotensin in the Nucleus Tractus Solitarii
I. Robin A. Barraco in Nucleus of the Solitary Tract, 2019
Along with being a specific arginyl aminopeptidase and leucine aminopeptidase inhibitor,16-18 bestatin may also be a potent blocker of alanyl and leucyl aminopeptidase.16 Based on these properties and presently available data on amino acid sequences and peptide degradation, it follows that the neuropeptides most likely to be protected by this degradative enzyme blocker may at least include, albeit not exclusively, neurotensin, angiotensin III, substance P, and somatostatin.
Immunity and Cancer Therapy: Present Status and Future Projections 1
Ronald H. Goldfarb, Theresa L. Whiteside in Tumor Immunology and Cancer Therapy, 2020
Bacterial products were the first to be tested within this group of agents, BCG being probably one of the most extensively studied (8,9). Significant antitumor effects were seen in patients with melanoma (18) and with superficial bladder tumors (19); in both cases in situ or regional administration were most effective. A direct antitumor effect was unlikely; indeed inoculation of BCG into one melanoma nodule led also to the regression of distant non-inoculated nodules. Although the mechanism of action of BCG has not been unequivocally clarified, it seems likely that activation of cells of the monocytic lineage is a relevant factor. This idea is corroborated also by the unique macrophage stimulating activity of MTP-PE (20), a synthetic analog of muramyl dipeptide, the smallest subunit of BCG that retains the adjuvant effect (21). Other bacterial products that have been tested clinically with uncertain success include C. parvum. Nocardia cell wall, streptococcal preparation OK432 (22) and FK565. Polysaccharide preparations such as Krestin, lentinan or glucans (22) have also been used in patients with a variety of neoplasias, especially in Japan, in conjunction with chemotherapeutic treatments. Although the majority of these preparations seems to provide non-specific immunoaugmentation, and are of some benefit to the patient in reducing the negative impact of opportunistic infections, rigorous evidence for antitumor effects mediated by an augmentation of host defense mechanisms is not available in most cases. In addition, modern oncologists are reluctant to use preparations not purified to homogeneity. It is conceivable that a synthetic preparation of a well characterized active principle may ultimately prove to have clinical utility. For example, Krestin has been shown to have augmenting effects on the mRNA of specific lymphokines (23) and this might lead to interesting applications after the active principles of this preparation have been completely characterized. Other curative products used in recent years as immunoaugmenting agents include the peptides tuftsin and bestatin (22).
Time matters – in vitro cellular disposition kinetics help rationalizing cellular potency disconnects
Published in Xenobiotica, 2022
Birk Poller, Sophie Werner, Norbert Domange, Lina Mettler, Richard R. Stein, Jacqueline Loretan, Markus Wartmann, Bernard Faller, Felix Huth
The transcellular permeability assay in MDCK-KO cells has been described in detail by Huth et al. (Huth et al. 2021). In brief, cells were seeded on Transwell 96-well plate inserts (Corning, Tewksbury, MA), at a density of 1.5 × 105 cells/mL and grown for 4 days. Each compound was dosed in triplicate in the apical donor compartment at a final concentration of 10 µM in Hanks’ balanced salt solution (HBSS) at pH 7.4 containing 10 mM HEPES, 100 nM bafilomycin and 0.02% w/v bovine serum albumin (BSA). The same assay buffer was used in the basolateral acceptor compartment with the exception of a higher BSA concentration (5%). Cells were incubated with the compounds for 2 h at 37 °C, and flux was measured in the apical-to-basolateral direction. Bestatin was included in each well to monitor integrity of the cell monolayer and only wells with a Papp <1.5 × 10−6 cm/s were accepted. Drug concentrations in the donor and acceptor compartments were measured by liquid chromatography mass spectrometry (LC-MS), using a six-point calibration curve, glyburide as an analytical internal standard (see details below).
Resveratrol Blunts Mitochondrial Loss in Slow and Mixed Skeletal Muscle Phenotypes of Non-Human Primates following a Long-Term High Fat/Sugar Diet
Published in Journal of Dietary Supplements, 2023
Jon-Philippe K. Hyatt, Rafael de Cabo, Julie A. Mattison
To ensure homogenous total protein isolation, SOL and PLT muscle sample chunks from the approximate muscle belly were mounted on cork and cut cross-sectionally using a cryostat (CM1950; Leica, Buffalo Grove, IL). Approximately 30–80 15 µm-thick cross sections were acquired, which equated to ∼50–100 mg sampled from each muscle. Samples were then bead homogenized for 2.5 min at 3,000 rpm in 10-volume ice-cold buffer (pH 7.8) containing 50 mM Tris-HCl, 2 mM EDTA, 2 mM EGTA, 10% glycerol, 1% Triton-X, and a 1% v/v final concentration of a protease and phosphatase inhibitor cocktail (PPC1010; Sigma, St. Louis, MO) containing 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, aprotinin, bestatin hydrochloride, N-(trans-Epoxysuccinyl)-L-leucine 4-guanidinobutylamide, leupeptin, pepstatin A, cantharidin, (–)-p-Bromolevamisole oxalate, and calyculin A. After homogenization, the samples were centrifuged at 12,000 g for 10 min at 4 °C, and the supernatant was transferred to clean tubes in a biological safety cabinet, and then frozen at −80 °C.
Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chao Wang, Yujing Zhang, Lingyu Shi, Shanbo Yang, Jing Chang, Yingjie Zhong, Qian Li, Dongming Xing
Statistics were performed using data extracted from PubMed and PROTAC-DB to determine the frequency of various IAP ligands used in SNIPERs (Figure 5) 37,38. The LCL-161 derivative was the most commonly used, with approximately 31% of SNIPERs employing its structure. It was closely followed by bestatin, with lower occurrence of MV1 derivatives and IAP ligand 4 at 10% and 9%, respectively. Other IAP ligands were less common, with less than 3% representation.
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