By Heather Hobbs


BRINGING YOU THE LATEST NEWS & EVENTS FROM THE SCIENCE INDUSTRY Masking technique strategy targets proteins


chemical tool able to study the function of these proteins and manipulate them in ways not previously possible.


“There is growing interest in targeting SH2 domains using small molecules because they are so prevalent and involved in so many interactions of so many proteins that determine key cellular processes,” explained Professor Ciulli, Director of the CeTPD.


CeTPD research team pictured (l-r) Alessio Ciulli, Kevin Haubrich, Dylan Lynch and Beth Forrester


Research led by Professor Alessio Ciulli at the University of Dundee’s recently opened Centre for Targeted Protein Degradation (CeTPD) has unlocked a class of proteins known as suppressor of cytokine signalling (SOCS), using a newly designed molecule that is able to target and bind to a protein class previously considered undruggable by using a masking technique to enter the cell.


SOCS proteins contain a crucial structural portion called the SH2 domain and the SOCS2 protein is involved in many diseases, including cancer and inflammatory diseases; until now, no small molecule has ever been generated that successfully inhibits the protein.


One of the major research interests of the Ciulli Lab is the targeting of E3 ligase complexes that can initiate the recycling of proteins in the cell, by earmarking abnormal proteins for destruction. It is possible to induce this process using carefully designed drugs, known as PROTACs, which have the ability to tightly bind to a certain E3 ligase - SOCS2 is an example of one such ligase. The newly developed molecule does exactly that, offering a


“When these processes go awry in disease, by targeting these interactions we have a very effective way to block the progression of the disease, and even revert it. Beyond this, in separate approaches we can co-opt or hijack key signalling proteins as in case of our targeted SOCS2 in order to re-direct their activity against disease-causing proteins, in a therapeutically beneficial manner. To enable either of these strategies, a critical first step involves finding small molecules that provide suitable starting points. With this work, we have done just that, for a protein class that had to date proven recalcitrant to these types of approaches.”


SOCS2 and its SH2 domain have very shallow pockets which are difficult to effectively target with molecules that have the properties required to become drugs. The natural binder of the SH2 domain contains a phosphate group, which is highly negatively charged. To develop the molecule, the Dundee team worked to evolve around the SH2 domain pocket, designing a compound that could engage with the protein binding site. However, the compound developed by the Dundee researchers also contains a phosphate unit, causing significant problems for getting it to enter the cell. By ‘masking’ the charged group, the researchers were able to successfully target the protein.


“The charged group is repelled by the negatively charge surface of the cell and so it keeps the drug on its exterior. One strategy to overcome this is to mask the charged group in a sort of Trojan Horse allegory,” explained Dr Sarath Ramachandran, who was a postdoctoral researcher in the Ciulli Lab at the time of the work.


“Groups that mask the charge are incorporated, which allows the drug to enter the cell. Once inside, a spontaneous chemical process mediated by the environment inside the cell happens, which tears apart such groups to ‘unmask’ the drug. This is akin to the Greeks jumping out of the horse inside which they were hiding. This releases the ‘active’ drug, allowing it to engage our target protein – much akin to the Greeks now being free to attack the city of Troy.


“Then, by permanently latching onto the protein we can block the target and prevent it from recruiting its native interacting proteins, providing a new research tool that will be useful to study the biological role and downstream signalling of SOCS2. This opens an opportunity to develop new therapeutics that target this protein and allows us to study and further target the protein in ways not previously possible.”


Professor Ciulli added, “In the short-term, other medicinal chemists and cell biologists will benefit from our new molecule, which can be used to study the SOCS2 protein in detail – namely its cellular function and downstream effects. On a larger timescale, our compound can be further elaborated into potential new drugs, for the treatment of cancer and other diseases.”


The work, funded by the European Research Council (ERC) and the Innovative Medicine Initiative 2 consortium EUbOpen, was spearheaded by postdoctoral researchers Dr Sarath Ramachandran and Dr Nikolai Makukhin, working as a multi-disciplinary team with other researchers in the Ciulli Lab including Dr Kevin Haubrich, Dr Dylan Lynch and MRes student Beth Forrester.


Published in Nature Communications. More information online: ilmt.co/PL/BBW1


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EU funding supports neurodegenerative diseases project


The protein TDP-43 (green) forms small clusters with an important regulatory function in the cell nucleus (Credit: Yelyzaveta Zadorozhna)


The protein TDP-43, important for biochemical process and present in all cells of our body, is a current subject of scrutiny as it can aggregate into large clumps in the brain, which could be linked to degenerative diseases such as Alzheimer’s and other dementias. Pursuing this line of research, a team led by Professor Dorothee Dormann from Johannes Gutenberg University Mainz (JGU), has been awarded a €2 million European Research Council (ERC) Consolidator Grant for the TDP Assembley Project, currently investigating the role of smaller scale groupings of these proteins in healthy cells.


Preliminary work has indicated that smaller assemblies of TDP-43 proteins might play an important role in regulatory processes, for example in the reading of genetic information and RNA production. Using methods from synthetic biology, she aims to artificially trigger various TDP-43 assemblies and investigate the resulting changes in cells. “The aim is to understand both the normal assembly process in healthy cells and the changes that lead to degenerative diseases when the assemblies become too large or too solid,” explained Dormann. Such abnormal protein clumps not only cause problems in the brain but also lead to a malfunction of the regulatory processes that the smaller assemblies normally carry out. In her research, Dormann will address the question of consequences of losing these small TDP-43 assemblies.


This research is especially important for developing future drugs to treat neurodegenerative diseases because drugs that prevent the aggregation of TDP-43 may also interfere with the smaller TDP-43 assemblies that are important for the body. A precise understanding of the functions of the assemblies is therefore required as well as knowledge of how the assembly process can be controlled from the early stages to the formation of large aggregates.


EU Consolidator Grants are awarded to outstanding individual scientists working on ground-breaking research. Dorothee Dormann, Professor of Molecular Cell Biology at JGU and Adjunct Director at the Institute of Molecular


Biology (IMB) in Mainz, is co-spokesperson of the Collaborative Research Center ‘Polymer Concepts for Understanding Cellular Functions’ (CRC 1551) and spokesperson of its integrated Research Training Group, both funded by the German Research Foundation. She is also a Principal Investigator in the research network EMTHERA (Emerging therapeutic strategies against infections, inflammation and immune-mediated diseases), with which Mainz University is applying for funding as a Cluster of Excellence in the German Excellence Strategy competition. Dormann has received numerous awards for her research achievements, including the Heinz Maier- Leibnitz Prize 2014 and the Paul Ehrlich and Ludwig Darmstaedter Prize for Young Researchers 2019.


More information online: ilmt.co/PL/bV0O 61769pr@reply-direct.com


Dorothee Dormann (Credit: Anton Pfurtscheller)


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