Proteins are essential to all known forms of life and participate in virtually every process within cells. Life sciences in the post-genomic era have to face the enormous challenges of identifying and characterising therapeutic and functional relevant proteins. Recent advances in automation and miniaturization facilitated the development of femto molar scale peptide libraries in microchip format - An emerging key technology to gain molecular level insight into proteins and their interactions.
Microarray Based Development of Protein Super Binders
We produce and apply such microarrays by combining the principles of synthetic chemistry, the processes of living organisms and modern automatization technologies with the ultimate goal to uncover novel therapeutic principles and stimulate the development of novel biopharmaceuticals. Using this approach we also aim to complement other driving technologies within Biology and Medical Sciences. To this end, we turn peptides, peptide-derived compounds as well as nanobody variants into compact high affinity binders with optimized selectivity profiles – Herein called “Protein Super Binders”. Due to their comparable small size and superior binding properties, such molecules make ideal protein labels when combined with fluorescent moieties. Thus help to unleash the full potential of high-end microscopy, allowing for virtually molecular structural resolution and quantitative information about the distribution of the target proteins in cellular context.
We are a joint initiative of the Department of Biotechnology and Biophysics of the Biocenter and the Rudolf Virchow Center for Experimental Biomedicine. We are supported by the program “Excellent Ideas” of the University of Würzburg.
9 August 2018
David Baumstark and Rico Petermann decided to support us to further develop and apply our peptide microarray technology platform!
7 August 2018
Congratulations to Rochelle and Steven for their great work on the collybistin protein that was just accepted in Nature Communications! We identified an exclusive binding of collybistin to the GABAAR-α2-subunit. - Notably, the first report of a high-affinity protein interaction for both proteins. Based on these results Rochelle created knock-in mice and demonstrated that this interaction is critical for the correct targeting and stabilisation of distinct α2-containing GABAAR clusters. She found that interfering with this protein interaction resulted in spontaneous seizures during development, accompanied by early mortality. Surviving mice have increased anxiety-like behavior and EEG abnormalities that are responsive to α2-selective benzodiazepines, revealing a novel therapeutic potential for these compounds. Publication
30 June 2018
Daniel Otzen just published his recent insight into the mechanism of functional Amyloid Formation. Using our microarray-based approach we identified specific motifs that are implicated in amyloid formation. These could lay the foundation for development of peptide-based amyloid inhibitors. Publication
19 June 2018
Vladimir Khayenko (MSc Pharmacy) started today. He will analyse protein interactions in microchip format and turn the identified binding hot-spots into fluorescent probes for high-end microscopy applications.
2 May 2018
We welcome biomedicine student Elisa Speth and senior scientist Dr. Shuang-Yan Wang. Dr. Shuang-Yan Wang joined us from Prof. John Robinsons group in Zürich where he developed highly specific cyclic peptidomimetics antibiotics in close cooperation with Polyphor.
18 May 2018
Our research is now supported by the Fonds der Chemischen Industrie (FCI). It is intended as start-up aid for high-performance junior research groups. The funding will be used within the next three years to specifically support the development of our independent research area. The award is given based on outstanding academic achievement and scientific qualification.
15 January 2018
Dr. Shuang-Yan Wang will join our lab as a senior researcher in March 2018. He will map receptor interactions in microchip format and then use the identified binding hot-spots as a starting point for the development of novel nanobodies and antibody mimetics.
Hines, R., Maric, H.M., Hines, D., Modgil, A., Panzanelli, P., Nakamura, Y., Nathanson, A., Cross, A., Deeb, T., Brandon, N., Davies, P., Fritschy, J.M., Schindelin, H., Moss, S. (2018) Developmental seizures and mortality result from reducing GABAA Receptor α2 subunit interaction with collybistin. Nature Communications, 9, 3130 (2018) doi: 10.1038/s41467-018-05481-1
Bleem, A., Christiansen, G., Madsen, D.J., Maric, H.M., Strømgaard, K., Bryers, J.D., Daggett, V., Meyer, R.L., Otzen, D.E., (2018) Protein Engineering Reveals Mechanisms of Functional Amyloid Formation in Pseudomonas aeruginosa Biofilms, Journal of Molecular Biology (2018) doi.org/10.1016/j.jmb.2018.06.043
Büchel G., Carstensen A., Mak K.Y., Roeschert I., Leen E., Sumara O., Hofstetter J., Herold S., Kalb J., Baluapuri A., Poon W, Kwok C, Chesler L, Maric H.M., Rickman D.S., Wolf E., Bayliss R., Walz S., Eilers M. Association with Aurora-A Controls N-MYC-Dependent Promoter Escape and Pause Release of RNA Polymerase II during the Cell Cycle. Cell Reports, Volume 21 , Issue 12 , 3483 – 3497 (2018) doi 10.1016/j.celrep.2017.11.090
Maric, H. M.*, Hausrat, T. J., Neubert, F., Dalby, N.O., Doose S., Sauer M., Kneussel M., Strømgaard K. (2017), Gephyrin-Binding Peptides Visualize Post-Synaptic Sites and Modulate Neurotransmission, Nature Chemical Biology, 13, 153–160 (2017) doi: 10.1038/nchembio.2246
(*First authorship and shared corresponding authorship)
Cheng J., Sahani S., Hausrat T. J., Yang J. W., Ji H., Schmarowski N., Endle H., Liu X., Li Y., Bottche R., Radyushkin K., Maric H. M., Hoerder-Suabedissen A., Molnar Z., Prouvot P. H., Trimbuch T., Ninnemann O., Huai J., Fan W., Visentin B., Sabbadini R., Strømgaard K., Stroh A., Luhmann H. J., Kneussel M., Nitsch R. Vogt J. (2016). Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling. Neuron 92(1): 126-142. doi: 10.1016/j.neuron.2016.08.035
Maric H. M., Kasaragod V. B., Haugaard-Kedström L., Hausrat T. J., Kneussel, M., Schindelin, H. and Strømgaard, K. (2015), Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors. Angewandte Chemie International Edition 2015, 54, p. 490–494. doi: 10.1002/anie.201409043
Selected as Hot Paper – Outstanding importance in a rapidly evolving field of high current interest
Maric, H. M.*, Kasaragod, V. B.*, Schindelin, H. (2014), Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin. Nature Communications 2014, 5(5767). doi: 10.1038/ncomms6767
(*shared first authorship)
Maric, H. M., Kasaragod, V. B., Schindelin, H. (2014), Modulation of the Gephyrin-Glycine Receptor Affinity by Multivalency. ACS Chemical Biology 2014, 9(11), p. 2554–2562. doi: 10.1021/cb500303a
Maric, H. M., Mukherjee J., Tretter, V., Moss, S. J., & Schindelin, H. (2011), Gephyrin-mediated γ-Aminobutyric Acid Type A and Glycine Receptor Clustering Relies on a Common Binding Site.The Journal of Biological Chemistry 2011, 286(49), p. 42105-42114. doi:10.1074/jbc.M111.303412
Mukherjee J., Kretschmannova K.*, Gouzer G.*, Maric H. M.*, Ramsden S., Tretter V., Harvey K., Davies P.A., Triller A., Schindelin H., Moss S.J. (2011), The residence time of GABAARs at inhibitory synapses is determined by direct binding of the receptor α1 subunit to gephyrin. The Journal of Neuroscience 2011, 31(41), p. 14677-87. doi: 10.1523/JNEUROSCI.2001-11.2011
(*shared second authorship.)
Tretter V., Kerschner B., Milenkovic I., Ramsden S. L., Ramerstorfer J., Saiepour L., Maric H.M., Moss S. J., Schindelin H., Harvey R. J., Sieghart W., Harvey K. (2011), Molecular basis of the GABAA α3 subunit interaction with the clustering protein gephyrin. The Journal of Biological Chemistry 2011, 286(43): p. 37702-11. doi: 10.1074/jbc.M111.291336.
Tretter V., Mukherjee J., Maric H. M., Schindelin H., Sieghart W., Moss S. J. (2012), Gephyrin, the enigmatic organizer at GABAergic synapses. Frontiers in Cellular Neuroscience 2012. 6: p. 23. doi: 10.3389/fncel.2012.00023.
Junior Group Leader at the Rudolf Virchow Center of the University of Würzburg (since January 2018)
|04/2015-07/2017||Assistant Professor, Center for Biopharmaceuticals, University of Copenhagen, Denmark|
|07/2013-03/2015||Postdoctoral Fellow, Lundbeck Trust, Copenhagen, Denmark|
|12/2012-06/2013||Postdoctoral Fellow, Career Development Fellowship, GSLS Würzburg|
|2008 - 2012||Ph.D. Student, Rudolf Virchow Center, Würzburg, Germany|
|2002 - 2008||MSc (Diplom) in Chemistry, University of Würzburg, Germany |
Co-inventor of a novel biopharmaceutical substance PA 2015 70783 and PCT DK2016 050369 and co-author of 12 peer-reviewed publications with an accumulated impact of +95, so far yielding 329 citations.
Fellowships and Awards
Excellent Ideas Program(2018 - 2022)
Fonds der chemischen Industrie „Exzellente Ideen“ Programm (2018)
Hoerslev Fonden (2018)
Torben og Alice Frimodts Fond (2017)
Brødrene Hartmanns Fond (2016)
Lundbeck Fellowship (2013 - 2015)
GSLS Career Development Fellowship (2012 - 2013)
Review Editor for Frontiers in Molecular Neuroscience
Scientific advisory boards: Reviewer for the Vienna Science and Technology Fund
Commissioner for chemical safety in the Rudolf Virchow Center
Winner of the 24th Bavarian Team Kendo Championship 2018
Supervisor – Biomedicine
Member of the Chair for Biophysics and Biotechnology
Biophysics and Molecular Biotechnology
Lecture – Thermodynamics