News from the Institute
New therapeutic targets preventing SARS-CoV-2 replication.
Researchers around IBC2 Group Leader Christian Münch comprehensively analyzed the response of human host cells to SARS-CoV-2 infection and identified growth factor receptor (GFR) signaling as essential for SARS-CoV-2 replication. GFR signaling plays important roles in various diseases. Five different drugs targeting GFR signaling prevented production of SARS-CoV-2 particles in cells. These results are now published in Molecular Cell.
Molecular differences between SARS and SARS-CoV-2
Scientists from IBC2 and collaborating teams identified the papain-like protease (PLpro) of SARS-CoV-2 as an essential viral enzyme and potential weak spot. PLpro is required for the processing of viral polypeptides and the assembly of new viral particles within human cells. In addition, SARS-CoV-2 uses this enzyme to dampen the anti-viral immune response, helping the virus to modulate the host’s immune system to its own benefit. By this, the virus can easily multiply and spread further. The team has demonstrated that pharmaceutical targeting of PLpro by a non-covalent inhibitor (GRL-0617) blocks virus spread and increases anti-viral immunity in human epithelial cells, the prime site of pathogen entry. The respective results are now published in Nature.... (read more)
Weak binding affinity between two interacting proteins is very beneficial for cellular signaling cascades, ensuring their dynamic ON/OFF regulation. However, weak affinity of protein-protein interactions (PPIs) also represents a major obstacle in chemical screening. The root of the problem is a lack of approaches for targeting such interactions, ultimately limiting our abilities to discover novel medicines. In an article published in Cell Chemical Biology, Maculins et al., 2020 describe an innovative approach to chemical screening.... (read more)
As published in Molecular Cell today, the Müller group has discovered a unique link between SUMO-mediated nuclear protein quality control and cytosolic stress granules (SGs). SGs are ribonucleotide particles that represent a prototypic example of membrane-less organelles. SG assembly is an important stress response that limits protein synthesis to avoid further influx into overloaded proteostasis systems. Typically, SGs rapidly disassemble when stress resolves. This process is impaired in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, due to mutations in RNA-binding proteins such as FUS or TDP-43. Jan Keiten-Schmitz and coworkers now found that the proper disassembly of SGs upon release of heat or arsenite stress requires both SUMO chain formation and the SUMO-targeted ubiquitin ligase (StUbL) RNF4. Strikingly, they could show that this pathway limits the accumulation of an ALS-causing FUS mutant in SGs. Taken together, these data demonstrate that the StUbL pathway is intricately linked to the dynamics of SGs and might be exploited therapeutically in ALS.... (read more)
Despite COVID-19 quickly developing to a world-wide pandemic, treatment options remain limited. The mechanisms by which SARS-CoV-2 enters cells, how the cell responds to infection, and which therapeutic approaches could stop viral replication remain unclear. In a manuscript published today in the renowned journal Nature, IBC2 group leader Christian Münch, together with Jindrich Cinatl (Institute of Medical Virology, University Hospital Frankfurt), provide with answers to these questions. Using SARS-CoV-2 isolated from COVID-19 patients in Frankfurt, they established a cellular model to study coronavirus infection. Using a recently developed novel translation proteomics method (https://doi.org/10.1016/j.molcel.2019.11.010), they analysed how viral infection changes cellular protein synthesis and abundance. This revealed several cellular pathways strongly modulated upon SARS-CoV-2 infection. Strikingly, using drugs targeting these pathways – some of which are approved for use in other diseases – prevented SARS-CoV-2 replication in cells. This reveals potential new therapeutic strategies for specific COVID-19 treatments and have been picked up for ongoing (ribavirin) and planned (2-deoxy-glucose) clinical trials.