Discovering compounds and mechanisms
for inhibiting ferroptosis,
a form of regulated, nonapoptotic cell death, has been of great interest
in recent years. In this study, we demonstrate the ability of XJB-5-131,
JP4-039, and other nitroxide-based lipid peroxidation mitigators to
prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells.
Several analogues of the reactive oxygen species (ROS) scavengers
XJB-5-131 and JP4-039 were synthesized to probe structure–activity
relationships and the influence of subcellular localization on the
potency of these novel ferroptosis suppressors. Their biological activity
correlated well over several orders of magnitude with their structure,
relative lipophilicity, and respective enrichment in mitochondria,
revealing a critical role of intramitochondrial lipid peroxidation
in ferroptosis. These results also suggest that preventing mitochondrial
lipid oxidation might offer a viable therapeutic opportunity in ischemia/reperfusion-induced
tissue injury, acute kidney injury, and other pathologies that involve
ferroptotic cell death pathways.
Highlights d Bacteria confer host cells with resistance to NAMPT inhibitors (NAMPTis) d Bacteria produce deamidated NAD precursors and prevent NAD depletion d Bacteria rescue NAMPTi-induced toxicity through nicotinamidase PncA d Oral NAM and NR boost in vivo NAD largely via microbiotadependent deamidated pathway
24Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all 25 cell types, plays an essential role in diverse cellular processes including metabolism, DNA 26 repair, and aging 1 . NAD metabolism is critical to maintain cellular homeostasis in response to 27 the environment, and disruption of this homeostasis is associated with decreased cellular NAD 28 levels in aging 2 . Conversely, elevated NAD synthesis is required to sustain the increased 29 metabolic rate of cancer cells 3,4 . Consequently, therapeutic strategies aimed to both upregulate 30 NAD (i.e. NAD-boosting nutriceuticals) or downregulate NAD (inhibitors of key NAD synthesis 31 enzymes) are being actively investigated 5-10 . However, how this essential metabolic pathway is 32 impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom 33 cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD 34 biosynthesis. Bacteria confer cancer cells with the resistance to inhibitors of NAMPT, the rate 35 limiting enzyme in the main vertebrate NAD salvage pathway. Mechanistically, a microbial 36 nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a key precursor in the 37 alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective 38 effect. This bacteria-enabled resistance mechanism that allows the mammalian host to bypass 39 the drug-induced metabolic block represents a novel paradigm in drug resistance. This host-40 microbe metabolic interaction also enables bacteria to dramatically enhance the NAD-boosting 41 efficiency of nicotinamide supplementation in vitro and in vivo, demonstrating a crucial role of 42 microbes, gut microbiota in particular, in organismal NAD metabolism. 43 44 45 46 3 47 mycoplasma-infected cells (Fig. 2D, right). Taken together, our results indicate that mycoplasma 132 primarily affect NAD-mediated energy metabolism in host cells. 133The amidated (via NAM) and deamidated (via NA) salvage pathways of NAD 134 biosynthesis are isolated in vertebrate cells due to lack of a nicotinamidase activity that converts 135 NAM to NA (Fig. 1A). In contrast, multiple bacteria species encode nicotinamidases 19 . Given 136 the dramatic upregulation of the deamidated NAD precursors (NA and NAR) in mycoplasma-137 infected medium and cells ( Fig. S5B and 2B), we hypothesized that protection from NAMPTi by 138
Many drug candidates fail therapeutic development because of poor aqueous solubility. We have conceived a computer-aided strategy to enable polymeric micelle-based delivery of poorly soluble drugs. We built models predicting both drug loading efficiency (LE) and loading capacity (LC) using novel descriptors of drug-polymer complexes. These models were employed for virtual screening of drug libraries, and eight drugs predicted to have either high LE and high LC or low LE and low LC were selected. Three putative positives, as well as three putative negative hits, were confirmed experimentally (implying 75% prediction accuracy). Fortuitously, simvastatin, a putative negative hit, was found to have the desired micelle solubility. Podophyllotoxin and simvastatin (LE of 95% and 87% and LC of 43% and 41%, respectively) were among the top five polymeric micelle-soluble compounds ever studied experimentally. The success of the strategy described herein suggests its broad utility for designing drug delivery systems.
Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 indole substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series of methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC 50 s from low nanomolar to double-digit micromolar. Surprisingly, we found that the trifluoromethoxy-analogue was biochemically a better match of the trifluoromethyl-substituted lead structure than a pentafluorosulfanyl-analogue. Moreover, in spite of their almost equivalent strongly electron-depleting effect on the indole core, pentafluorosulfanyl-and nitro-derivatives were found to exhibit a 430-fold difference in p97 inhibitory activities. Conversely, the electronically divergent C-5 methyl-and nitro-analogues both showed low nanomolar activities.
Haliclonin A (1), a macrocyclic diamide of a novel skeletal class, was isolated from the marine sponge Haliclona sp. collected from Korean waters. The structure of this compound was determined using a combination of spectroscopic and chemical analyses. The new compound exhibited moderate cytotoxicity and antibacterial activity against diverse microbial strains.
a) T max : time of the C max ; C max : maximal observed concentration; AUC all : area under the curve from the time of dosing to the time of the last observation; b) Significance S versus W groups: *p < 0.05, **p < 0.01. See Table S4 (Supporting Information) for detailed analysis of the polymer and drug exposure and clearance.
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