Exploring and understanding biological systems at the molecular level with a tool set offered by modern chemistry is the common motif of my research interests. As a Chemical Biologist I find it intriguing to use small organic compounds, either derived from nature or by rational design, to study complex biological processes with a resolution that is neither offered by genetic nor biochemical approaches. Consequently the research in my lab is centered on the interface of biology and organic synthetic chemistry, including the synthesis of diversity-oriented-synthesis (DOS) derived libraries for biochemical and in vitro screening, the development of novel assay systems for high-throughput screening, as well as the development of small molecule tool compounds for target identification and imaging application.
Zhao WN, Hylton NK, Wang J, Chindavong PS, Alural B, Kurtser I, Subramanian A, Mazitschek R, Perlis RH, Haggarty SJ Activation of WNT and CREB signaling pathways in human neuronal cells in response to the Omega-3 fatty acid docosahexaenoic acid (DHA). Mol Cell Neurosci. 2019;99:103386 - PMID: 31202891 - PMCID: PMC7001743 - DOI: 10.1016/j.mcn.2019.06.006
Ho M, Chen T, Liu J, Dowling P, Hideshima T, Zhang L, Morelli E, Camci-Unal G, Wu X, Tai YT, Wen K, Samur M, Schlossman RL, Mazitschek R, Kavanagh EL, Lindsay S, Harada T, McCann A, Anderson KC, O'Gorman P, Bianchi G Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia. 2020;34(1):196-209 - PMID: 31142847 - PMCID: PMC6883144 - DOI: 10.1038/s41375-019-0493-x
Choudhary A, Manna D, Maji B, Gangopadhyay SA, Cox KJ, Zhou Q, Law B, Mazitschek R A singular system with precise dosing and spatiotemporal control of CRISPR-Cas9. Angew Chem Int Ed Engl. 2019;58(19):6285-6289 - PMID: 30834641 - PMCID: PMC7067309 - DOI: 10.1002/anie.201900788
Fagbami L, Deik AA, Herman JD, Singh K, Santos SA, Bopp S, Lukens AK, Clish CB, Wirth DF, Mazitschek R The adaptive proline response in P. falciparum is independent of PfeIK1 and eIF2α signaling. ACS Infect Dis. 2019;5(4):515-520 - PMID: 30773881 - PMCID: PMC6747701 - DOI: 10.1021/acsinfecdis.8b00363
Zhao WN, Ghosh B, Tyler M, Lalonde J, Joseph NF, Kosaric N, Fass DM, Tsai LH, Mazitschek R, Haggarty SJ Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory. ACS Chem Neurosci. 2018;9(9):2262-2273 - PMID: 29932631 - DOI: 10.1021/acschemneuro.8b00116
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One major focus in my group is in the development of subtype specific modulators of chromatin modifying enzymes, such as histone deacetylase (HDAC) inhibitors. HDACs have originally been discovered as chromatin modifying enzymes, however, recent research suggests that regulation of non-histone proteins by acetylation is more abundant than originally anticipated and comparable to other posttranslational modifications. The development of HDAC inhibitors (as tool compounds or as drug) has paid little attention to subtype specificity, which is limiting the applicability of these compounds. Our goal is it to understand the features that convey selectivity and to develop tools to selectively study the function of HDACs isoforms (in particular class II enzymes) in in vivo and in vivo systems.
In addition I do have a strong interest in dieseases that are neglected by industrial research due to the lack of financial interest. In particular my group has been focusing on the discovery of novel antimalarials and the identification of previously untargeted pathways that are vital to the Plasmodium parasite and suitable for chemotherapeutic intervention. The identification of the molecular target(s) of active compounds will not only allow to study their underlying biology in P. falciparum but also accelerate the development of novel medicines.