Identification of Regulators for Ciliary Disassembly by a Chemical Screen

The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug induced liver injury (DILI) would be valuable in such situations. We used hepatocyte-specific expression of bacterial nitroreductase in zebrafish to cause temporally controlled liver damage. This transgenic line was used to run a whole organism based chemical screen in zebrafish larvae. In this screen we identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 also showed remarkable protective action in two independent toxicological models of liver injury caused by acetaminophen and Isoniazid. This suggests that BML-257 may have the potential to protect against multiple kinds of drug induced liver injury.

Download Full-text

A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors

PLoS Biology ◽

10.1371/journal.pbio.3001263 ◽

2021 ◽

Vol 19 (5) ◽

pp. e3001263

Author(s):

Alba Corman ◽

Dimitris C. Kanellis ◽

Patrycja Michalska ◽

Maria Häggblad ◽

Vanesa Lafarga ◽

...

Keyword(s):

Anticancer Agents ◽

Kinase Inhibitors ◽

Current Knowledge ◽

Mrna Translation ◽

Mtor Signaling Pathway ◽

Mechanism Of Toxicity ◽

Sphingosine Kinases ◽

Chemical Screen ◽

Approved Drugs ◽

Very High

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.

Download Full-text

Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus Infection

Journal of Biological Chemistry ◽

10.1074/jbc.m112.392142 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35324-35332 ◽

Cited By ~ 59

Author(s):

Oxana V. Denisova ◽

Laura Kakkola ◽

Lin Feng ◽

Jakob Stenman ◽

Ashwini Nagaraj ◽

...

Keyword(s):

Influenza A ◽

Treatment Options ◽

Antiviral Agents ◽

Cell Type ◽

Influenza A Viruses ◽

Novel Host ◽

Chemical Screen ◽

Species Specific ◽

Host Target ◽

Transcription And Replication

Influenza A viruses (IAVs) infect humans and cause significant morbidity and mortality. Different treatment options have been developed; however, these were insufficient during recent IAV outbreaks. Here, we conducted a targeted chemical screen in human nonmalignant cells to validate known and search for novel host-directed antivirals. The screen validated saliphenylhalamide (SaliPhe) and identified two novel anti-IAV agents, obatoclax and gemcitabine. Further experiments demonstrated that Mcl-1 (target of obatoclax) provides a novel host target for IAV treatment. Moreover, we showed that obatoclax and SaliPhe inhibited IAV uptake and gemcitabine suppressed viral RNA transcription and replication. These compounds possess broad spectrum antiviral activity, although their antiviral efficacies were virus-, cell type-, and species-specific. Altogether, our results suggest that phase II obatoclax, investigational SaliPhe, and FDA/EMEA-approved gemcitabine represent potent antiviral agents.

Download Full-text

A Chemical Screen Probing the Relationship between Mitochondrial Content and Cell Size

PLoS ONE ◽

10.1371/journal.pone.0033755 ◽

2012 ◽

Vol 7 (3) ◽

pp. e33755 ◽

Cited By ~ 35

Author(s):

Toshimori Kitami ◽

David J. Logan ◽

Joseph Negri ◽

Thomas Hasaka ◽

Nicola J. Tolliday ◽

...

Keyword(s):

Cell Size ◽

Mitochondrial Content ◽

Chemical Screen ◽

The Relationship

Download Full-text

Whole-Animal Chemical Screen Identifies Colistin as a New Immunomodulator That Targets Conserved Pathways

mBio ◽

10.1128/mbio.01235-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 17

Author(s):

Yun Cai ◽

Xiou Cao ◽

Alejandro Aballay

Keyword(s):

Transcription Factor ◽

Immune Responses ◽

Immune Activation ◽

Bacterial Infections ◽

Mitogen Activated Protein Kinase ◽

Resistant Bacteria ◽

Long Term Outcome ◽

Gram Negative ◽

Content Type ◽

Chemical Screen

ABSTRACTThe purpose of this study was to take advantage of the nematodeCaenorhabditis elegansto perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds, that are capable of activating a conserved p38/PMK-1 mitogen-activated protein kinase pathway required for innate immunity. One of these drugs, the last-resort antibiotic colistin, protected against infections by the Gram-negative pathogensYersinia pestisandPseudomonas aeruginosabut not by the Gram-positive pathogensEnterococcus faecalisandStaphylococcus aureus. Protection was independent of the antibacterial activity of colistin, since the drug was administered prophylactically prior to the infections and it was also effective against antibiotic-resistant bacteria. Immune activation by colistin is mediated not only by the p38/PMK-1 pathway but also by the conserved FOXO transcription factor DAF-16 and the transcription factor SKN-1. Furthermore, p38/PMK-1 was found to be required in the intestine for immune activation by colistin. Enhanced p38/PMK-1-mediated immune responses by colistin did not reduce the bacterial burden, indicating that the pathway plays a role in the development of host tolerance to infections by Gram-negative bacteria.IMPORTANCEThe innate immune system represents the front line of our defenses against invading microorganisms. Given the ever-increasing resistance to antibiotics developed by bacterial pathogens, the possibility of boosting immune defenses represents an interesting, complementary approach to conventional antibiotic treatments. Here we report that the antibiotic colistin can protect against infections by a mechanism that is independent of its microbicidal activity. Prophylactic treatment with colistin activates a conserved p38/PMK-1 pathway in the intestine that helps the host better tolerate a bacterial infection. Since p38/PMK-1-mediated immune responses appear to be conserved from plants to mammals, colistin may also activate immunity in higher organisms, including humans. Antibiotics with immunomodulatory properties have the potential of improving the long-term outcome of patients with chronic infectious diseases.

Download Full-text

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2−/− phenotype

Scientific Reports ◽

10.1038/s41598-019-56995-7 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

A. Metzner ◽

J. D. Griffiths ◽

A. J. Streets ◽

E. Markham ◽

T. Philippou ◽

...

Keyword(s):

Kinase Inhibitors ◽

Polycystic Kidney ◽

Novel Treatments ◽

Compound Libraries ◽

Chemical Screen ◽

Autosomal Dominant Polycystic Kidney ◽

Major Chemical ◽

End Stage ◽

Alternative Drugs

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α−androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

Download Full-text