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Nitric Oxide as a Signaling Molecule in the Systemic Inflammatory Response to LPS
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Sepsis is a response to infection in which an attack on the microvascular endothelium plays a key pathogenic role. Blood vessel injury results in micro-circulatory ischemia, reduced systemic vascular resistance, hypo-tension, impaired organ perfusion, and derangements in oxygen delivery. Acute respiratory distress syndrome, myocardial depression, splanchnic ischemia, liver and kidney toxicity, and altered cerebral blood flow can follow and represent the critical multiorgan manifestations of these initial hemodynamic changes. The evidence that NO participates in these pathological changes has recently been reviewed (27–29). Two findings derived from studying patients undergoing sepsis provide important support for the conclusion that NO mediates vascular dysfunction in this disease in human beings. First, the oxidized products of NO, nitrite and nitrate, are elevated in sepsis (30–32), and the levels of these metabolites correlate with changes in two important hemodynamic parameters, mean arterial pressure, and systemic vascular resistance. Second, a number of clinical studies have shown that substrate analog inhibitors of NO synthases, when administered in sufficient quantities to reduce circulating nitrites and nitrates, partially correct the abnormal hemodynamic parameters of septic patients (33,34).
The Reaction Mechanism
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The mechanism proposed by Goodall322 also accounts for the observations made by Stubbe et al.830,832 that propionyl-CoA carboxylase and transcarboxylase catalyze the elimination of F- from β-fluoropropionyl-CoA with concomitant decarboxylation of carboxybiotin. In this case, the binding of the acceptor molecule, β-fluoropropionylCoA, induces carboxybiotin to move into the second subsite where the enolate anion of carboxybiotin is formed. The anion abstracts a proton from the C-2 atom of the substrate analog (as it would in the normal reaction), but instead of the C-2 atom attacking the carboxyl group of carboxybiotin, fluoride is eliminated from fluoropropionyl-CoA. (Stubbe et al.830,831 suggest several reasons why fluoride elimination occurs in preference to carboxylation.) The net result is formation of acrylyl-CoA and enol carboxybiotin; when the acrylyl-CoA dissociates, the carboxybiotin reverts to its ureido form and water now has access to the carboxybiotin which hydrolyzes by the mechanism already described. It should be remembered that fluoride elimination only occurs when the biotin is in the carboxybiotin form.
Tipranavir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Tipranavir, like other HIV protease inhibitors, prevents the formation of infectious virions by inhibiting the HIV protease enzyme that cleaves viral polyproteins in HIV-1-infected cells and in virions released from those cells. Unlike older peptidomimetic HIV protease inhibitors, saquinavir, ritonavir, and indinavir, tipranavir does not block HIV protease by acting as a substrate analog. It is a nonpeptide molecule, originally developed by three-dimensional structure design-based strategies at Pharmacia and Upjohn, that selectively inhibits the active site of HIV protease. Tipranavir exhibits potent activity against all wild-type HIV-1 isolates, including some of those that are highly resistant to earlier protease inhibitors.
Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease
Published in Xenobiotica, 2019
Ozlem Dalmizrak, Kerem Teralı, Osman Yetkin, I. Hamdi Ogus, Nazmi Ozer
Protein–ligand interaction profiling of the crystal structure of soman-aged human BChE in complex with the substrate analog BTCh (PDB entry: 1P0P) revealed that the tertiary amine group of BTCh was anchored in the active-site gorge of the enzyme via a π–cation interaction with the side-chain aromatic ring of W82 in the choline-binding pocket (distance: 4.32 Å). The same tertiary amine group was also in sufficient proximity to form a salt bridge with the side-chain carboxyl group of E197 near the catalytic subsite (distance: 4.17 Å). The stability of BTCh in the active-site gorge of human BChE was further enhanced by hydrophobic interactions with F329 at the choline-binding subsite, Y332 at the peripheral anionic site, and A328 (all within 4.00 Å of BTCh). When the predicted structure of human BChE in complex with fluoxetine was superimposed on the crystal structure of soman-aged human BChE in complex with the substrate analog BTCh, fluoxetine was seen to be involved in extensive steric clashes with BTCh (Figure 1(D)). This implies that the active-site gorge of human BChE cannot accommodate both fluoxetine and BTCh at the same time.
Inhibition of O-acetylserine sulfhydrylase by fluoroalanine derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Nina Franko, Konstantinos Grammatoglou, Barbara Campanini, Gabriele Costantino, Aigars Jirgensons, Andrea Mozzarelli
Given the observed spectral changes, it can be concluded that F-Ala behaves as a substrate analog of OASS, as previously observed for β-chloroalanine30 and that the intermediate α-aminoacrylate is oriented within the active site in such a way to disfavour the reaction with any active site residue. This finding is not surprising considering that OASS has evolved to stabilise an α-aminoacrylate intermediate ready to react with the incoming nucleophilic sulfide. In addition, it has been reported for alanine racemase29,36 that the partition ratio between α-aminoacrylate hydrolysis and Michael addition on the adduct formed from the F-Ala is 820:1, a further indication of the very poor reactivity of this species in the enzyme active site.
A patent review of MALT1 inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Isabel Hamp, Thomas J. O’Neill, Oliver Plettenburg, Daniel Krappmann
In the patent, the inventors broadly claim that inhibition of MALT1 protease activity with a small molecule, an RNA-based inhibitor, or a substrate analog will impair differentiation of functional human Treg cells from naive T cells in vitro. As exemplified by example 2 g (IC50 = 9.9 nM in biochemical activity assay [82]), corresponding to Novartis compound MLT-985 (24) (Figure 6), MALT1 inhibition yielded a concentration-dependent loss of Treg cells in human PBMCs. The inventors present data supporting the concept that the mechanism of Treg cell depletion may be beneficial for the treatment of cancer by using the syngeneic MB49 mouse bladder cancer model. Treatment with MLT-985 furthermore yielded a strong loss of Treg cells in the tumor tissue and the tumor-draining lymph nodes (TDLN) following 4 days of treatment. Essentially, MALT1 inhibitor treatment did not affect absolute Teff cell numbers, but by decreasing Treg cells, an approximately 1300% increase in the Teff/Treg cell ratio in the TDLN can be achieved in the MB49 cancer model. Thus, the patent concludes that anti-proliferative activity of the compounds is not via direct inhibition of MALT1 in cancer cells but functions via targeting Treg cells to decrease their numbers and thereby increase host effector T cell functions to combat the cancer. The patent claims that MALT1 inhibitor-dependent Treg cell reduction could be beneficial when combined with other therapies, including treatment with checkpoint inhibitors, effector T cell stimulants, adoptive T cell transfer, or administration of tumor antigens. WO2018/141749 [82] is solely a use patent, focusing on claiming the use of MALT1 inhibitors for immuno-oncological applications. Thus, the example compounds noted in the patent are urea-based compounds claimed or explicitly described in the first Novartis patent WO2015/181747 [75].