Biology subjects

Corman, A.

Publications and source records attributed to Corman, A..

3 recordsLinked to original sources

bioRxiv2025

PI3K/mTOR activity sensitizes cancer cells to nucleolar stress

Drugs targeting nucleoli and generating nucleolar stress (NS) such as RNA Polymerase I inhibitors have shown anticancer properties with some progressing to clinical trials. However, the mechanisms that modulate the sensitivity to NS remain poorly understood, which has limited the design of clinical trials on patients most likely responding to these therapies. To get a panoramic view of the genetic determinants that shape the response to NS in cancer cells, we conducted genome-wide CRISPR screens in cells treated with 2 independent RNA Polymerase I inhibitors: Actinomycin D (ActD) and BMH-21. As expected, mutations known to regulate the response to NS such as P53 or RB1 increased the resistance to both drugs. On the other hand, the toxicity of RNA Pol I inhibitors was increased in the context of mutations that enhance PI3K/mTOR signaling. Surprisingly, we found mutations that sensitized to ActD but increased the resistance to BMH-21, revealing that, while both drugs are used as RNA Pol I inhibitors, the must have additional unknown targets. Together our study provides a global landscape of the mechanisms that modulate the sensitivity to NS-inducing agents and illustrate the need for an in-depth analysis of the mechanism of toxicity of drugs, particularly when these are advancing to clinical use.

cell biology↗

bioRxiv2023

Discovery of a novel inhibitor of macropinocytosis with antiviral activity

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a new molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using High-Throughput Microscopy, where we identified new chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as Monkeypox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present a new molecule that inhibits viral entry via the endocytic route, offering a new alternative to prevent viral infection.

pharmacology and toxicology↗

bioRxiv2020

A chemical screen identifies a link between lipid metabolism and mRNA translation

mRNA translation is one of the most energy-demanding processes for living cells, alterations of which have been frequently documented in human disease. Using recently developed technologies that enable image-based quantitation of overall translation levels, we here conducted a chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. Consistent with current knowledge, inhibitors of the mTOR signaling pathway were the most represented class among translation suppresors. 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, which activates the integrated stress response (ISR). Accordingly, the impact of SPHK inhibitors on translation is alleviated by the concomitant inhibition of ISR kinases. On the other hand, and despite the large number of molecules tested, our study failed to identify chemicals capable of substantially increasing mRNA translation, raising doubts on to what extent translation can be supra-physiologically stimulated in mammalian cells. In summary, our study provides the first comprehensive characterization of the effect of known drugs on protein translation and has helped to unravel a new link between lipid metabolism and mRNA translation in human cells.

molecular biology↗