Half- Sandwich cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype

2020 ◽  
Author(s):  
Sofia Alexandra Milheiro ◽  
Joana Gonçalves ◽  
Ricardo Lopes ◽  
Margarida Madureira ◽  
Lis Lobo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Blood Stage ◽  
Nuclear Accumulation ◽  
Selective Absorption ◽  
Asexual Parasite ◽  
Single Digit ◽  
Liver Stage ◽  
Dual Stage ◽  
Fluorescent Compounds ◽  
Half Sandwich

<p><a>A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of general formula [(</a>η<sup>5</sup>-C<sub>5</sub>R<sub>5</sub>)Ru(PPh<sub>3</sub>)(N-N)][PF<sub>6</sub>], a scaffold hitherto unfeatured in the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2 and artemisinin-resistant IPC5202 <i>Plasmodium falciparum</i> strains, and the liver stage of <i>P. berghei</i>. The best performing compounds displayed dual-stage activity, with single-digit nM IC<sub>50</sub> values against blood stage malaria parasites, nM activity against liver stage parasites, and residual cytotoxicity against mammalian cells (HepG2, Huh7). Parasitic absorption/distribution of 7-nitrobenzoxadiazole-appended fluorescent compounds <b>Ru4</b> and <b>Ru5</b> was investigated by confocal fluorescence microscopy, revealing parasite-selective absorption in infected erythrocytes and nuclear accumulation of both compounds. The lead compound <b>Ru2</b> impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized <i>P. falciparum</i> 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials.</p>

Half- Sandwich cyclopentadienylruthenium(II) Complexes: A New Antimalarial Chemotype

2020 ◽  
Author(s):  
Sofia Alexandra Milheiro ◽  
Joana Gonçalves ◽  
Ricardo Lopes ◽  
Margarida Madureira ◽  
Lis Lobo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Blood Stage ◽  
Nuclear Accumulation ◽  
Selective Absorption ◽  
Asexual Parasite ◽  
Single Digit ◽  
Liver Stage ◽  
Dual Stage ◽  
Fluorescent Compounds ◽  
Half Sandwich

<p><a>A small library of “half-sandwich” cyclopentadienylruthenium(II) compounds of general formula [(</a>η<sup>5</sup>-C<sub>5</sub>R<sub>5</sub>)Ru(PPh<sub>3</sub>)(N-N)][PF<sub>6</sub>], a scaffold hitherto unfeatured in the toolbox of antiplasmodials, was screened for activity against the blood stage of CQ-sensitive 3D7-GFP, CQ-resistant Dd2 and artemisinin-resistant IPC5202 <i>Plasmodium falciparum</i> strains, and the liver stage of <i>P. berghei</i>. The best performing compounds displayed dual-stage activity, with single-digit nM IC<sub>50</sub> values against blood stage malaria parasites, nM activity against liver stage parasites, and residual cytotoxicity against mammalian cells (HepG2, Huh7). Parasitic absorption/distribution of 7-nitrobenzoxadiazole-appended fluorescent compounds <b>Ru4</b> and <b>Ru5</b> was investigated by confocal fluorescence microscopy, revealing parasite-selective absorption in infected erythrocytes and nuclear accumulation of both compounds. The lead compound <b>Ru2</b> impaired asexual parasite differentiation, exhibiting fast parasiticidal activity against both ring and trophozoite stages of a synchronized <i>P. falciparum</i> 3D7 strain. These results point to cyclopentadienylruthenium(II) complexes as a highly promising chemotype for the development of dual-stage antiplasmodials.</p>

Small Molecules Effective Against Liver and Blood Stage Malarial Infection

2019 ◽  
Vol 18 (23) ◽  
pp. 2008-2021 ◽  
Author(s):  
Snigdha Singh ◽  
Neha Sharma ◽  
Charu Upadhyay ◽  
Sumit Kumar ◽  
Brijesh Rathi ◽  
...  
Keyword(s):  
Drug Targets ◽  
Malaria Parasite ◽  
Blood Stage ◽  
Culture Methods ◽  
Liver Stage ◽  
Malarial Infection ◽  
Dual Stage ◽  
New Treatment ◽  
Global Threat

Malaria is a lethal disease causing devastating global impact by killing more than 8,00,000 individuals yearly. A noticeable decline in malaria related deaths can be attributed to the most reliable treatment, ACTs against P. falciparum. However, the cumulative resistance of the malaria parasite against ACTs is a global threat to control the disease and, therefore the new effective therapeutics are urgently needed, including new treatment approaches. Majority of the antimalarial drugs target BS malarial infection. Currently, scientists are eager to explore the drugs with potency against not only BS but other life stages such as sexual and asexual stages of the malaria parasite. Liver Stage is considered as one of the important drug targets as it always leads to BS and the infection can be cured at this stage before it enters into the Blood Stage. However, a limited number of compounds are reported effective against LS malaria infection probably due to scarcity of in vitro LS culture methods and clinical possibilities. This mini review covers a range of chemical compounds showing efficacy against BS and LS of the malaria parasite’s life cycle collectively (i.e. dual stage activity). These scaffolds targeting dual stages are essential for the eradication of malaria and to evade resistance.

scholarly journals Dihydroquinazolinone Inhibitors of Proliferation of Blood and Liver Stage Malaria Parasites

2013 ◽  
Vol 58 (3) ◽  
pp. 1516-1522 ◽  
Author(s):  
Emily R. Derbyshire ◽  
Jaeki Min ◽  
W. Armand Guiguemde ◽  
Julie A. Clark ◽  
Michele C. Connelly ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Berghei ◽  
Mammalian Cells ◽  
Blood Stage ◽  
Malaria Parasites ◽  
Liver Stage ◽  
Content Type ◽  
Minimal Toxicity ◽  
Structure Activity ◽  
Further Development

ABSTRACTDrugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds—dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles—with promising activity against the liver stage. Focused structure-activity studies on the dihydroquinazolinone scaffold revealed several molecules with excellent potency against both blood and liver stages. One promising early lead with dual activity is 2-(p-bromophenyl)-3-(2-(diethylamino)ethyl)-2,3-dihydroquinazolin-4(1H)-one with 50% effective concentrations (EC50s) of 0.46 μM and 0.34 μM against liver stagePlasmodium bergheiANKA and blood stagePlasmodium falciparum3D7 parasites, respectively. Structure-activity relationships revealed that liver stage activity for this compound class requires a 3-dialkyl amino ethyl group and is abolished by substitution at theortho-position of the phenyl moiety. These compounds have minimal toxicity to mammalian cells and are thus attractive compounds for further development.

scholarly journals The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alyssa N. Coyne ◽  
Jeffrey D. Rothstein
Keyword(s):  
Nuclear Pore Complex ◽  
Mammalian Cells ◽  
Nuclear Accumulation ◽  
Nuclear Pore ◽  
Dependent Manner ◽  
Structured Illumination Microscopy ◽  
Neuronal Nuclei ◽  
Complex Injury ◽  
Sporadic Als ◽  
Human Neurons

AbstractNuclear pore complex injury has recently emerged as an early and significant contributor to familial and sporadic ALS disease pathogenesis. However, the molecular events leading to this pathological phenomenon characterized by the reduction of specific nucleoporins from neuronal nuclear pore complexes remain largely unknown. This is due in part to a lack of knowledge regarding the biological pathways and proteins underlying nuclear pore complex homeostasis specifically in human neurons. We have recently uncovered that aberrant nuclear accumulation of the ESCRT-III protein CHMP7 initiates nuclear pore complex in familial and sporadic ALS neurons. In yeast and non-neuronal mammalian cells, nuclear relocalization of CHMP7 has been shown to recruit the ESCRT-III proteins CHMP4B, CHMP2B, and VPS4 to facilitate nuclear pore complex and nuclear envelope repair and homeostasis. Here, using super resolution structured illumination microscopy, we find that neither CHMP4B nor CHMP2B are increased in ALS neuronal nuclei. In contrast, VPS4 expression is significantly increased in ALS neuronal nuclei prior to the emergence of nuclear pore injury in a CHMP7 dependent manner. However, unlike our prior CHMP7 knockdown studies, impaired VPS4 function does not mitigate alterations to the NPC and the integral transmembrane nucleoporin POM121. Collectively our data suggest that while alterations in VPS4 subcellular localization appear to be coincident with nuclear pore complex injury, therapeutic efforts to mitigate this pathogenic cascade should be targeted towards upstream events such as the nuclear accumulation of CHMP7 as we have previously described.

scholarly journals A Humanized Mouse Model for Plasmodium vivax to Test Interventions that Block Liver Stage to Blood Stage Transition and Blood Stage Infection

iScience ◽  
2020 ◽  
Vol 23 (8) ◽  
pp. 101381
Author(s):  
Carola Schäfer ◽  
Wanlapa Roobsoong ◽  
Niwat Kangwanrangsan ◽  
Martino Bardelli ◽  
Thomas A. Rawlinson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Plasmodium Vivax ◽  
Blood Stage ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Liver Stage ◽  
Blood Stage Infection ◽  
Stage Transition ◽  
Stage Infection

scholarly journals Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules

2015 ◽  
Vol 112 (6) ◽  
pp. 1785-1790 ◽  
Author(s):  
Chih-Chao Yang ◽  
Hillary K. Graves ◽  
Ivan M. Moya ◽  
Chunyao Tao ◽  
Fisun Hamaratoglu ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Basal Cell ◽  
Mammalian Cells ◽  
Adherens Junctions ◽  
Hippo Pathway ◽  
Tumor Formation ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Downstream Effectors ◽  
The Hippo Pathway

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical–basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non–cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non–cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

scholarly journals Bioactivity of Spongian Diterpenoid Scaffolds from the Antarctic Sponge Dendrilla antarctica

Marine Drugs ◽  
2020 ◽  
Vol 18 (6) ◽  
pp. 327 ◽  
Author(s):  
Alexandre Bory ◽  
Andrew J. Shilling ◽  
Jessie Allen ◽  
Ala Azhari ◽  
Alison Roth ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Natural Products ◽  
Leishmania Donovani ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Chemical Library ◽  
Single Digit ◽  
Liver Stage ◽  
New Compounds ◽  
The Antarctic ◽  
Small Chemical

The Antarctic sponge Dendrilla antarctica is rich in defensive terpenoids with promising antimicrobial potential. Investigation of this demosponge has resulted in the generation of a small chemical library containing diterpenoid secondary metabolites with bioactivity in an infectious disease screening campaign focused on Leishmania donovani, Plasmodium falciparum, and methicillin-resistant Staphylococcus aureus (MRSA) biofilm. In total, eleven natural products were isolated, including three new compounds designated dendrillins B–D (10–12). Chemical modification of abundant natural products led to three semisynthetic derivatives (13–15), which were also screened. Several compounds showed potency against the leishmaniasis parasite, with the natural products tetrahydroaplysulphurin-1 (4) and dendrillin B (10), as well as the semisynthetic triol 15, displaying single-digit micromolar activity and low mammalian cytotoxicity. Triol 15 displayed the best profile against the liver-stage malaria parasites, while membranolide (5) and dendrillin C (11) were strong hits against MRSA biofilm cultures.

scholarly journals A yeast model system for functional analysis of β-catenin signaling

2002 ◽  
Vol 158 (6) ◽  
pp. 1067-1078 ◽  
Author(s):  
Margaret S. Lee ◽  
Karen A. D'Amour ◽  
Jackie Papkoff
Keyword(s):  
Reporter Gene ◽  
Gene Transcription ◽  
Nuclear Export ◽  
Mammalian Cells ◽  
Glycogen Synthase ◽  
Nuclear Export Signal ◽  
Signal Transduction Pathway ◽  
Model System ◽  
Nuclear Accumulation ◽  
Molecular Events

We have developed a novel Saccharomyces cerevisiae model system to dissect the molecular events of β-catenin (β-cat) signaling. Coexpression of mammalian β-cat with TCF4 or LEF1 results in nuclear accumulation of these proteins and a functional complex that activates reporter gene transcription from constructs containing leukocyte enhancer factor (LEF)/T cell factor (TCF) response elements. Reporter transcription is constitutive, requires expression of both β-cat and TCF4 or LEF1, and is not supported by mutated LEF/TCF binding elements or by TCF4 or LEF1 mutants. A cytoplasmic domain of E-cadherin or a functional fragment of adenomatous polyposis coli (APC) protein (APC-25) complexes with β-cat, reduces β-cat binding to TCF4, and leads to increased cytoplasmic localization of β-cat and a reduction in reporter activation. Systematic mutation of putative nuclear export signal sequences in APC-25 decreases APC-25 binding to β-cat and restores reporter gene transcription. Additional β-cat signaling components, Axin and glycogen synthase kinase 3β, form a multisubunit complex similar to that found in mammalian cells. Coexpression of the F-box protein β-transducin repeat-containing protein reduces the stability of β-cat and decreases reporter activation. Thus, we have reconstituted a functional β-cat signal transduction pathway in yeast and show that β-cat signaling can be regulated at multiple levels, including protein subcellular localization, protein complex formation, and protein stability.

scholarly journals MondoA, a Novel Basic Helix-Loop-Helix–Leucine Zipper Transcriptional Activator That Constitutes a Positive Branch of a Max-Like Network

2000 ◽  
Vol 20 (23) ◽  
pp. 8845-8854 ◽  
Author(s):  
Andrew N. Billin ◽  
Alanna L. Eilers ◽  
Kathryn L. Coulter ◽  
Jennifer S. Logan ◽  
Donald E. Ayer
Keyword(s):  
Transcriptional Activation ◽  
Nuclear Export ◽  
Mammalian Cells ◽  
Leucine Zipper ◽  
Functional Characterization ◽  
Nuclear Accumulation ◽  
Cytoplasmic Localization ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix

ABSTRACT Max is a common dimerization partner for a family of transcription factors (Myc, Mad [or Mxi]), and Mnt [or Rox] proteins) that regulate cell growth, proliferation, and apoptosis. We recently characterized a novel Max-like protein, Mlx, which interacts with Mad1 and Mad4. Here we describe the cloning and functional characterization of a new family of basic helix-loop-helix–leucine zipper heterodimeric partners for Mlx termed the Mondo family. MondoA forms homodimers weakly and does not interact with Max or members of the Myc or Mad families. MondoA and Mlx associate in vivo, and surprisingly, they are localized primarily to the cytoplasm of cultured mammalian cells. Treatment of cells with the nuclear export inhibitor leptomycin B results in the nuclear accumulation of MondoA and Mlx, demonstrating that they shuttle between the cytoplasmic and nuclear compartments rather than having exclusively cytoplasmic localization. MondoA preferentially forms heterodimers with Mlx, and this heterocomplex can bind to, and activate transcription from, CACGTG E-boxes when targeted to the nucleus via a heterologous nuclear localization signal. The amino termini of the Mondo proteins are highly conserved among family members and contain separable and autonomous cytoplasmic localization and transcription activation domains. Therefore, Mlx can mediate transcriptional repression in conjunction with the Mad family and can mediate transcriptional activation via the Mondo family. We propose that Mlx, like Max, functions as the center of a transcription factor network.

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