Wednesday, June 29, 2022

Shining some light on the obscure proteome

Group Leader in Chemical Proteomics, Dr. Guillaume Médard, and his research group in the lab.
 Credit: Uli Benz / TUM

Mass-spectrometry based proteomics is the big-data science of proteins that allows to monitor the abundances of thousands of proteins in a sample at once. It is therefore a particularly well suited readout to discover which proteins are targeted by any small molecule. An international research team has investigated this using chemical proteomics.

Histone deacetylase (HDAC) inhibitors are a class of drugs used in oncology. An international research team involving scientists at the Technical University of Munich (TUM), Cornell University in Ithaca (USA), the German Cancer Research Center (DKFZ) in Heidelberg and Martin Luther University of Halle-Wittenberg has now investigated the effects of some HDAC drugs in more detail. The scientists wanted to know whether those epidrugs engage proteins other than the HDACs which they are designed to inhibit.

“To do so, target deconvolution by chemical proteomics is the method of choice. Hence, we first made new chemical tools - the so called affinity matrices - that would allow us to systematically profile the HDACs,” explains Dr. Guillaume Médard, group leader for chemical proteomics at the TUM chair of Proteomics and Bioanalytics led by Prof. Bernhard Küster.

“I profiled 53 drugs”, details Severin Lechner, doctoral candidate at the TUM School of Life Sciences. “Most of them, but not all, hit their intended HDAC target. However there were some surprises. Drugs used in hundreds of scientific studies were not as selective as assumed. Many had additional targets that were not previously known.

These results highlight the power of proteomic approaches that probe the binding to thousands of proteins at once. Finally, several molecules with outstanding selectivity were identified, making them HDAC inhibitors of choice for future scientific studies.

“The most unexpected finding was that MBLAC2 is an off-target of half of the profiled molecules,” Lechner continues. This protein is not well characterized but coincidentally, the team of Prof. Maurine Linder in Cornell researched on it at the same time. The two groups in Germany and the USA collaborated and confirmed that the protein is indeed hindered to perform its function in presence of the drugs.

With the group of Prof. Michael Pfaffl at TUM, hinted by unexplained phenotypic effects of some drugs, Lechner proved that MBLAC2 inhibition or knock down leads to accumulation of extracellular vesicles in the extracellular space. Extracellular vesicles are small membrane-bounded particles secreted by cells and transported through the whole body to transmit biomolecules and information between cells and tissues.

“We are excited because we uncovered a new player in this field of biology that notably encompasses exosomes, which play crucial roles in neurology, immunology and oncology,” explains Médard. “We are now designing molecules that only hit MBLAC2 so that we can probe this obscure protein in a range of model systems.”

This study will be useful to whomever wants to use HDAC inhibitors for probing biology or for therapeutic use. It helps choosing the right chemical tool. It is also a valuable set of data for medicinal chemists that need to understand how chemical structures relate to potency and selectivity to make tomorrow’s epidrugs.

Publications:
Severin Lechner, Martin Ian P. Malgapo, Christian Grätz, Raphael R. Steimbach, Agnes Baron, Patrick Rüther, Simon Nadal, Carmen Stumpf, Christina Loos, Xin Ku, Polina Prokofeva, Ludwig Lautenbacher, Tino Heimburg, Vivian Würf, Chen Meng, Mathias Wilhelm, Wolfgang Sippl, Karin Kleigrewe, Josch K. Pauling, Karl Kramer, Aubry K. Miller, Michael W. Pfaffl, Maurine E. Linder, Bernhard Kuster und Guillaume Médard (2022). Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target. In: Nature Chemical Biology.

Source/Credit: Technical University of Munich

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