42 research outputs found

    Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

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    Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.Chemistry and Chemical Biolog

    Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase

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    Toxoplasma gondii commonly infects humans and while most infections are controlled by the immune response, currently approved drugs are not capable of clearing chronic infection in humans. Hence, approximately one third of the world\u27s human population is at risk of reactivation, potentially leading to severe sequelae. To identify new candidates for treating chronic infection, we investigated a series of compounds derived from diversity-oriented synthesis. Bicyclic azetidines are potent low nanomolar inhibitors of phenylalanine tRNA synthetase (PheRS) in T. gondii, with excellent selectivity. Biochemical and genetic studies validate PheRS as the primary target of bicyclic azetidines in T. gondii, providing a structural basis for rational design of improved analogs. Favorable pharmacokinetic properties of a lead compound provide excellent protection from acute infection and partial protection from chronic infection in an immunocompromised mouse model of toxoplasmosis. Collectively, PheRS inhibitors of the bicyclic azetidine series offer promise for treatment of chronic toxoplasmosis

    Tetracyclines Modify Translation by Targeting Key Human rRNA Substructures

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    International audienceApart from their antimicrobial properties, tetracyclines demonstrate clinically validated effects in the amelioration of pathological inflammation and human cancer. Delineation of the target(s) and mechanism(s) responsible for these effects, however, has remained elusive. Here, employing quantitative mass spectrometry-based proteomics, we identified human 80S ribosomes as targets of the tetracyclines Col-3 and doxycycline. We then developed in-cell click selective crosslinking with RNA sequence profiling (icCL-seq) to map binding sites for these tetracyclines on key human rRNA substructures at nucleotide resolution. Importantly, we found that structurally and phenotypically variant tetracycline analogs could chemically discriminate these rRNA binding sites. We also found that tetracyclines both subtly modify human ribosomal translation and selectively activate the cellular integrated stress response (ISR). Together, the data reveal that targeting of specific rRNA substructures, activation of the ISR, and inhibition of translation are correlated with the anti-proliferative properties of tetracyclines in human cancer cell lines

    Distortion Metrics for Robotic Sensor Networks

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    Abstract — We examine the problem of planning the trajectory of a robotic vehicle to gather data from a deployment of stationary sensors. The robotic vehicle and the sensors are equipped with wireless modems (e.g., radio in terrestrial environments or acoustic in underwater environments), which provide noisy communication across limited distances. In such scenarios, the robotic vehicle can improve its efficiency by planning an informed data gathering trajectory. Prior work has proposed information theoretic performance metrics for these problems based on mutual information, but such metrics do not properly account for stochastic variations in the quantity being measured. We propose a novel performance metric for data gathering in robotic sensor networks based on the concept of squared error distortion. This metric provides a principled approach for modeling source variations and communication limitations during data collection. We analyze the formal properties of the distortion function, and we propose a sampling-based motion planning algorithm for optimizing data gathering tours for minimal distortion. We compare the proposed algorithms in simulation, and we show that distortion metrics provide significant improvements in data gathering efficiency. I

    Screening cascade for DOS screen (A) and potency comparison of hits from the DOS library between the novel axenic and intramacrophage assay (B).

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    <p>A: Screening cascade. Numbers of compounds that passed and failed the hit selection criteria are shown respectively in green and red. Numbers marked with an asterisk indicate that the selectivity window is unknown and may be ≥ 10 (no effect seen in HepG2 assay, activity in the cidal axenic assay pEC50<5.3). The cascade starts with screening 9,907 compounds in the novel axenic assay at a single concentration (nov. axenic SP). Identified hits are processed in potency format in both the novel axenic assay (axenic pot., for activity confirmation) and HepG2 assay (HepG2 pot., toxicity information against the human cell line HepG2). Active compounds that provide a ≥ 10-fold toxicity window are processed in the intramacrophage potency assay (intramac. pot.) for hit confirmation, resulting in 24 hits. B: Comparison of novel axenic and intramacrophage mean pEC<sub>50</sub> values for 141 compounds. The size of the markers is inversely related to the toxicity against the THP-1 cells (i.e. high toxicity–small symbol). Colour is by series (green: Ortho Azetidine Nitrile, blue: Azetidine Nitrile, orange: Povarov, red: SnAr 8-ortho, yellow: other). Data set represents three biological replicates for the novel axenic assay (with the exception of one compound with two replicates only) and at least two replicates for the intramacrophage assay.</p

    Screening cascade.

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    <p>Novel axenic assay is primary, single concentration (SP) entry to the cascade, followed by confirmation, assessment of potency and selectivity using the novel axenic assay and a mammalian counterscreen assay (HepG2) in potency mode (pot.). Potent and selective hits are then profiled in the intramacrophage assay.</p

    Library screen with novel axenic assay, comparison with intracellular results.

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    <p>15,667 compounds were screened in the novel axenic assay at 15μM. Comparison with the intracellular assay shows that 67 of the hits are also active in the intracellular assay whereas 71 of the hits are not. 280 novel axenic assay inactive compounds were hits in the intracellular assay, 170 of these compounds showed toxicity in the intracellular assay (in single point mode, at 50μM, or less than 3-fold selectivity window in potency assay) and are therefore considered false positives in the intracellular assay. Potencies were determined for 110 non-toxic compounds in the novel axenic and intracellular assays. 13 compounds were inactive in the intracellular assay and are added to the false positive count (13 + 170 = 183). 97 compounds had confirmed activity in the intracellular assay; 42 of these compounds showed activity in the novel axenic assay, while 54 did not. (INMAC = intracellular assay). Hit criteria as described in Table A in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004094#pntd.0004094.s001" target="_blank">S1 Text</a>.</p
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