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The Interaction of Lipid A and Lipopolysaccharide with Human Serum Albumin
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Although native LPS also binds to HSA through its lipid A moiety, there are differences between free lipid A and LPS with respect to their interactions with HSA. This is probably attributable to differences in the physical states of lipid A and LPS. It has also become apparent that HSA and polymyxin B bind to different sites on the lipid A portion of LPS. Complexes of lipid A or LPS with albumin exhibit the full spectrum of biological activities (14,15), being in this respect similar to other serum factors that behave as LPS opsonins, such as the septins (59) and lipopolysaccharide-binding protein (13,60–64), while other serum proteins such as lysozyme (9,54,55) or bactericidal/permeability increasing protein (65–68) can either partially or completely neutralize endotoxin activity. This suggests that these LPS-binding proteins may recognize disparate regions on the endotoxin and, consequentially, present parts of the toxin molecule which are either toxically active or quiescent to target cells. A unique “toxophore” on the lipid A/LPS molecule has not yet been identified, and it is of relevance in this regard to note that the ability of polymyxin B to form ternary complexes with LPS bound to macromolecular ligands correlates with the retention of toxicity in the LPS-protein complexes. Both HSA and lysozyme (9,54,55), which, respectively, do not or only partially modify the activity of complexed LPS, permit noncompetitive interactions with polymyxin B and the consequent formation of ternary complexes, whereas proteins that neutralize endotoxin activity such as the Limulus anti-LPS factor (69) or the HA-1 A monoclonal antibody to lipid A (70), bind to LPS in a competitive manner. The elucidation of the structural basis of this phenomenon would be of value in structure-toxicity relationships in LPS and in designing specific endotoxin-sequestering agents. Upon a closer examination of the physical properties of such endotoxin-binding proteins, a rather intriguing trend became apparent: several proteins that only bind LPS and do not inhibit endotoxic activity are generally negatively charged at neutral pH with a pK of less than 7.0, while proteins that “sequester” LPS, inhibiting its toxicity, are basic with a much higher pK (Table 2). This observation, although preliminary and deserving of more careful and thorough scrutiny, might be a valuable tool in identifying potential molecular targets of lipopolysaccharide.
A public-private partnership for the express development of antiviral leads: a perspective view
Published in Expert Opinion on Drug Discovery, 2021
The ADME-TOX predictive array is expected to incorporate the individual methods based on diverse and preferably non-correlating principles. One approach is docking of the candidate to the structural models of the targets typically mediating toxicity [87]. Such toxicity-mediating off-targets are cytochromes P450, cardiomyocyte receptors, neuron receptors, key enzymes. Another approach includes machine-learning identification of the non-interpretable but correct patterns of future successful pharmaceuticals [88]. Yet other methods rely on the profiles of physical parameters of the candidates [89], 2D and 3D molecular fingerprints [90], toxophore presence [91], modeled permeability from physico-chemical properties [92]. Multiple freeware and commercially available packages quantify all ADME-TOX components individually and produce the integrated score to assess the ligand variants. The examples of the ready in-silico products are TOPKAT, SWISS-ADME, FAF-Drugs, PAINS, Discover Studio, Admet SAR, Pro-Tox II, ESOL, AdmetOpt, vNN. The lead variants can be also explored by non-computational approaches in collaboration with academia or start-ups, for example by using organoid arrays/body-on-chip setting [93,94]. The organoid assay read-outs can predict toxicity and metabolization [95,96] and these data can be also used as a training medium to differentiate between the approved drugs and Phase I failures.
The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy
Published in Expert Opinion on Drug Discovery, 2019
Najah Albadari, Shanshan Deng, Wei Li
Kresoxim-methyl analogues (12) were designed and showed to inhibit hypoxia-induced HIF-1 transcriptional activation with IC50 values of 0.60–0.94 μM in human colorectal cancer (HCT116) cells. They work by increasing the intracellular oxygen tension under hypoxic condition, and thus promoting the ubiquitin-dependent proteasomal degradation of HIF-1α and impairing its accumulation [166]. Kresoxim-methyl is a marketed synthetic analogue of strobilurin fungicide with the representative toxophore methyl methoxy-imino-acetate. It is a mitochondrial inhibitor specifically targets the cytochrome bc1 complex (complex III) of the mitochondrial electron transport chain by binding to its Q0 site; therefore, perturbs the ROS mitochondrial production responsible for hypoxia-dependent stabilization of HIF-1.
Army Liposome Formulation (ALF) family of vaccine adjuvants
Published in Expert Review of Vaccines, 2020
Carl R. Alving, Kristina K. Peachman, Gary R. Matyas, Mangala Rao, Zoltan Beck
Lipid A has been studied for decades to untangle the structural basis of its numerous endotoxin activities [46,47], and numerous reviews have summarized an amazing history of complex research [48,49]. As pointed out by Beutler and Rietschel ‘… endotoxic activity is not dependent on a single lipid-A constituent (toxophore group), but is dependent on a defined conformation (endotoxic conformation) that is determined by unique features of the primary structure, including steric factors, negative charge and hydrophobic domains’ [50].