Jelena Melesina
Dr. Jelena Melesina
Tel.
e-mail: jelenamelesina(at)gmail.com
Development of novel isoform-specific Sirtuin inhibitors
Sirtuins are NAD+-dependent protein deacylases that cleave off acetyl groups, as well as other acyl groups, from the ε-amino group of lysines in histones and other substrate proteins. They are considered as link between metabolism and epigenetics. The human genome encodes seven sirtuin isotypes, Sirt1-7. Dysregulation of human Sirt2 activity has been associated with the pathogenesis of cancer, inflammation, and neurodegeneration, thus making Sirt2 a promising target for pharmaceutical intervention. In previous work we have identified the sirtuin rearranging ligands (SirReals) as a novel class of highly potent Sirt2 inhibitors with proven cellular activity. Furthermore, these inhibitors showed a very high selectivity for Sirt2 among the sirtuin isotypes Sirt1-6. Extensive structure activity relationship studies in combination with crystal structures of Sirt2-SirReal complexes enabled us to elucidate the unique mode of Sirt2 selective inhibition mediated by the SirReals. Based on this knowledge we have developed a platform to generate Sirt2-selective affinity probes. A biotinylated Sirt2-selective affinity probe offers new applications for SirReals, such as biophysical characterization, fragment-based screening, and affinity pull-down assays. Within this project we will exploit this platform further to develop new Sirt2-selective affinity probes with specific functionalities, like fluorescent labels, HaloTag reactive linkers, hydrophobic tags, like adamantyl, to promote hydrophobic tagging–induced Sirt2 degradation, or a thalidomide-tag that should induce Cereblon-dependent Sirt2 degradation. These SirReal-based probes will be important tools for studying Sirt2 biology and encompass entities with therapeutic potential. Guided by the structural insight on Sirt2-selective inhibition obtained from Sirt2-SirReals co-crystal structures and molecular modelling studies, we will optimize the SirReals for better aqueous solubility for optimized biological evaluation. Finally, based on available crystal structures and docking studies we will rationally modulate the Sirt2 selectivity of the SirReals to use them as starting points to obtain selective inhibitors of other sirtuin isotypes. We will focus on the subtypes Sirt1 and 7 that are highly interesting and where potent and highly selective inhibitors are in great demand. Virtual screening and structure-based optimization will be used to provide novel chemotypes and optimized hits. These in turn will be valuable tools to study sirtuin biology and its therapeutic potential.
Funded by the DFG
Publications
2021
J. Melesina, C. V. Simoben, E. F. Bulbul, L. Praetorius, D. Robaa, W. Sippl. Strategies to Design Selective HDAC Inhibitors. ChemMedChem. 2021 Jan 11. doi:10.1002/cmdc.202000934. Online ahead of print
2020
K. Hoff, S. Mielniczuk, O. Agoglitta, M. T. Iorio, M. Caldara, E. F. Bulbul, J. Melesina, W. Sippl, R. Holl. Synthesis and biological evaluation of triazolyl-substituted benzyloxyacetohydroxamic acids as LpxC inhibitors. Bioorg Med Chem. 28(13):115529, 2020.
D. V. Kalinin, S. Kumar, J. M. Pfafenrot, A. Chakrabarti, J. Melesina, W. Sippl, C. Romier, M. Jung, R. Holl. Triazole-based smHDAC8 Inhibitors: Synthesis and Biological Evaluation. ChemMedChem. 15, 571-584, 2020.
D. Robaa, J. Melesina, C.Luise, W. Sippl. Structure-based design of epigenetic inhibitors. In: Mai A. (eds) Chemical Epigenetics. Topics in Medicinal Chemistry, vol 33. 2020. Springer, Cham. https://doi.org/10.1007/7355_2019_80
2019
D. Kalinin, O. Agoglitta, H. Van de Vyver, J. Melesina, S.Wagner, B. Riemann, M. Schäfers, W. Sippl, B. Löffler, and R. Holl. Proline-based Hydroxamates Targeting the Zinc-Dependent Deacetylase LpxC: Synthesis, Antibacterial Properties, and Docking Studies. Bioorg Med Chem. 27, 997-2018, 2019.
A. Dreger, O. K. O. Agoglitta, E. F. Bülbül J. Melesina, W. Sippl, and R. Holl. Chiral pool synthesis, biological evaluation and molecular docking studies of C-furanosidic LpxC inhibitors. ChemMedChem. 14, 871-886, 2019.
2018
M. Marek, T.B. Shaik, T. Heimburg, A. Chakrabarti, J. Lancelot, E. Ramos-Morales, C. Da Veiga, D. Kalinin, J. Melesina, D. Robaa, K. Schmidtkunz, T. Suzuki, R. Holl, E. Ennifar, R.J. Pierce, M Jung, W. Sippl, C. Romier. Dissecting the molecular basis of HDAC8 selective inhibition reveals specific active site structural and functional determinants. J Med Chem. 61, 10000-10016, 2018. doi:10.1021/acs.jmedchem.8b01087
T. Bayer, A. Chakrabarti, J. Lancelot, T. B. Shaik, K. Hausmann, J. Melesina, K. Schmidtkunz, M. Marek, F. Erdmann, M. Schmidt, D. Robaa, C. Romier, R. J. Pierce, M. Jung and W. Sippl. Synthesis, crystallization studies and in vitro characterization of novel cinnamic acid derivatives as SmHDAC8 inhibitors for the treatment of Schistosomiasis. Chem Med Chem, 2018 May 27. doi:10.1002/cmdc.201800238
J. Melesina, L. Praetorius, C. V. Simoben, D. Robaa, W. Sippl. Design of Selective HDAC Inhibitors: Rethinking Classical Pharmacophore. Future Med. Chem. 10, 1537-1540, 2018. doi.org/10.4155/fmc-2018-0125
Kahlert V, Prell E, Ohlenschläger O, Melesina J, Schumann M, Lücke C, Fischer G, Malešević M. Synthesis and biochemical evaluation of two novel N-hydroxyalkylated cyclosporin A analogs. Org Biomol Chem. 16(23):4338-4349, 2018 doi:10.1039/c8ob00980e.
R. Narozny, B. Lecointre, J. Senger, A. Chakrabarti, M. Jung, M. Marek, C. Romier, J. Melesina, W. Sippl, M. T. Borrello, L. Bischoff, A. Ganesan. Isoform selective HDAC6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity. Phil. Trans. R. Soc. B 373, 20170364, 2018. DOI:10.1098/rstb.2017.0364
C. V. Simoben, D. Robaa, A. Chakrabarti, K. Schmidtkunz, M. Marek, J. Lancelot, S. Kannan, J. Melesina, T. B. Shaik, R. J. Pierce, C. Romier, M. Jung and W. Sippl. A novel class of Schistosoma mansoni histone deacetylase 8 (HDAC8) inhibitors identified by structure-based virtual screening and in vitro testing. Molecules 23(3). pii: E566. doi:10.3390/molecules23030566
K. King, A.-T. Hauser, J. Melesina, W. Sippl and M. Jung. Carbamates as prodrugs and new warhead for HDAC inhibition. Molecules, 23, 321, 2018. doi:10.3390/molecules23020321 .
2017
T. Heimburg, F. R. Kolbinger, P. Zeyen, E. Ghazy, D. Herp, K. Schmidtkunz, J. Melesina, T. B. Shaik, F. Erdmann, M. Schmidt, C. Romier, D. Robaa, O. Witt, I. Oehme, M. Jung, and W. Sippl. Structure-based design and biological characterization of selective HDAC8 inhibitors with anti-neuroblastoma activity. J. Med. Chem 60, 10188-10204, 2017. DOI:10.1021/acs.jmedchem.7b01447
K. Stenzel, A. Chakrabarti, J. Melesina, F. K. Hansen, J. Lancelot, S. Herkenhöhner, B. Lungerich, M. Marek, C. Romier, R. J. Pierce, W. Sippl, M. Jung, T. Kurz. Alkoxyamide-based HDAC Inhibitors as Potent Inhibitors of HDAC8 from Schistosoma mansoni. Archiv der Pharmazie 350, 8. doi:10.1002/ardp.201700097 .
L. L. S. Scholte, M. M. Mourãa, F. Sviatopolk-Mirsky Paisa, J. Melesina, D. Robaa, A. C. Volpini, W. Sippl, R. J. Piercee, G. Oliveira, L. A. Nahum. Evolutionary relationships among protein lysine deacetylases of parasites causing neglected diseases. Infect Genet Evol. 53:175-188, 2017. doi:10.1016/j.meegid.2017.05.011 .
2016
A. Chakrabarti, J. Melesina, F. Kolbinger, I. Oehme, J. Senger, O. Witt, W. Sippl, M. Jung. Targeting histone deacetylase 8 (HDAC8) as a therapeutic approach to cancer and neurodegenerative diseases. Future Med Chem. 8, 1609-34, 2016. doi:10.4155/fmc-2016-0117 .
G. Tangherlinia, T. Torregrossa, O. Agoglitta, J. Melesina, W. Sippl, R. Holl. Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors. Bioorg. Med. Chem. Lett. 24,1032-44, 2016. doi:10.1016/j.bmc.2016.01.029.
T. Heimburg, A. Chakrabarti, M. Marek, J. Lancelot, J. Melesina, D. Robaa, F. Erdmann, M. Schmidt, R. J. Pierce, C. Romier, M. Jung and W. Sippl. Structure-Based Design and Synthesis of Novel Inhibitors targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis. J. Med. Chem, 59, 2423-35, 2016. DOI: 10.1021/acs.jmedchem.5b01478
2015
W. Lei, M. Kofler, G. Brosch, J. Melesina, W. Sippl, E. D Martinez, J. Easmon. 2-Benzazolyl-4-piperazin-1-ylsulfonylbenzenecarbohydroxamic acids as novel selective histone deacetylase-6 inhibitors with antiproliferative activity. PlosOne, 2015 Dec 23;10(12):e0134556. doi:10.1371/journal.pone.0134556.
J. Senger, J. Melesina, M. Marek, C. Romier, I. Oehme, O. Witt, W. Sippl and M. Jung. Synthesis and biological investigation of new selective histone deacetylase 6 (HDAC6) inhibitors. J. Med. Chem. 59, 1545–1555, 2016. DOI:10.1021/acs.jmedchem.5b01493
J. Melesina, C. Romier, R. Pierce, W. Sippl. Homology Modeling of Parasite Histone Deacetylases to Guide the Structure-Based Design of Selective Inhibitors. J. Mol. Graph. Mod. 62, 342-361, 2015. doi: 101016/j.jmgm.2015.10.006.
G. Tangherlinia, T. Torregrossa, O. Agoglitta, J. Melesina, W. Sippl, R. Holl. Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors. Bioorg. Med. Chem. Lett. 24,1032-44, 2016. doi:10.1016/j.bmc.2016.01.029.
2014
S. Kannan, J. Melesina, A.-T. Hauser, A. Chakrabarti, T. Heimburg,
K. Schmidtkunz, A. Walter, M. Marek, R. J. Pierce, C. Romier, M. Jung and W. Sippl
Discovery of Inhibitors of Schistosoma Mansoni HDAC8 by Combining Homology Modeling, Virtual Screening and In Vitro Validation
J Chem Inf Model. 54, 2433-50, 2014. DOI:10.1021/ci5004653
D. A Stolfa, M. Marek, J. Lancelot, A.-T. Hauser, A. Walter, E. Leproult, J. Melesina, T. Rumpf, J. M. Wurtz, J. Cavarelli, W. Sippl, R. J Pierce, C. Romier, M. Jung
Molecular basis for the anti-parasitic activity of a mercaptoacetamide derivative that inhibits histone deacetylase 8 (HDAC8) from the human pathogen Schistosoma mansoni
J. Mol. Biol. 426, 3442-53, 2014. DOI:10.1016/j.jmb.2014.03.007
M. Szermerski, J. Melesina, K. Wichapong, M. Löppenberg, J. Jose, W. Sippl, R. Holl.
Synthesis, Biological Evaluation and Molecular Docking Studies of Benzyloxyacetohydroxamic Acids as LpxC Inhibitors
Bioorg Med Chem Lett 22, 1016-28, 2014. DOI:10.1016/j.bmc.2013.12.057
Posters
2016
T. Bayer , J. Melesina, A. Chakrabarti, F. Erdmann, M. Marek, C. Romier, M. Schmidt, M. Jung, W. SipplHydroxamic Acids as Small Molecule Inhibitors for Parasitic Targets – Synthesis and Biological EvaluationDrug Innovation in Academia08.12 2016, Heidelberg
T. Heimburg, A. Chakrabarti, J. Melesina, K. Schmidtkunz, M. Marek, J. Lancelot, F. Erdmann, M. Schmidt, C. Romier, R. Pierce, M. Jung, W. Sippl. Development of 3-amido-benzhydroxamates as modulators of epigenetic targets for the treatment of schistosomiasis.Drug Innovation in Academia08.12. 2016, Heidelberg
T. Bayer, A. Chakrabarti , F. Erdmann, J. Melesina, M. Marek, C. Romier, M. Schmidt, M. Jung, W. SipplSynthesis and in vitro characterization of hydroxamic acids as small molecule inhibitors for epigenetic parasitic targetsDPhG Annual Meeting 2016 04.10.- 07.10.2016, München
T. Heimburg, A. Chakrabarti, J. Melesina, K. Schmidtkunz, M. Marek, J. Lancelot, F. Erdmann, M. Schmidt, C. Romier, R. Pierce, M. Jung, W. Sippl. Development of 3-amido-benzhydroxamates as modulators of epigenetic targets for the treatment of schistosomiasis.DPhG Annual Meeting 2016 04.10.- 07.10.2016, München
T. Bayer, A. Chakrabarti , F. Erdmann, J. Melesina, M. Marek, C. Romier, M. Schmidt, M. Jung, W. SipplSynthesis and in vitro characterization of hydroxamic acids as small molecule inhibitors for protozoal targets 3rd Freiburg Epigenetic Spring Meeting: Chemical Biology of Epigenetics10. - 13.04.2016, Freiburg, Germany
T. Heimburg, A. Chakrabarti, J. Melesina, K. Schmidtkunz, M. Marek, C. Romier, M. Schmidt, M. Jung, W. Sippl. Development of 3-amido-benzhydroxamic acids as modulators of epigenetic targets for the treatment of schistosomiasis. 3rd Epigenetic Spring Meeting: Chemical Biology of 3rd Freiburg Epigenetic Spring Meeting: Chemical Biology of Epigenetics10. - 13.04.2016, Freiburg, Germany
2015
T. Heimburg, A. Chakrabarti, J. Melesina, K. Schmidtkunz, M. Marek, J. Lancelot, C. Romier, R. Pierce, M. Schmidt, M. Jung, W. Sippl. Development of 3-amido-benzhydroxamic acids as small molecule inhibitors of smHDAC8 for the treatment of schistosomiasis. DPhG Annual Meeting 2015 23.09.-25.09.2015, Düsseldorf
T. Bayer, A. Chakrabarti , F. Erdmann, J. Melesina, M. Marek, C. Romier, M. Schmidt, M. Jung, W. Sippl. Synthesis and in vitro characterization of hydroxamic acids as small molecule inhibitors for protozoal targets. DPhG Annual Meeting 2015 23.09.-25.09.2013, Düsseldorf
J. Melesina, T. Heimburg, K. Wichapong, M. Schmidt, A. Chakrabarti, A. T. Hauser, C. Romier, R. J. Pierce, M. Jung, W. Sippl. Computer-aided design of small molecules targeting parasitic histone deacetylases. Central German Meeting on Bioinformatics26.-27.08.2015, Halle, Germany
J. Melesina, T. Heimburg, K. Wichapong, M. Schmidt, A. Chakrabarti, A. T. Hauser, C. Romier, R. J. Pierce, M. Jung, W. Sippl. Molecular modeling in development of inhibitors for flatworm histone deacetylases. Frontiers in Medicinal Chemistry15-18.03.2015, Marburg, Germany
2014
J. Melesina, T. Heimburg, K. Wichapong, M. Schmidt, A. Hauser, C. Romier, R. Pierce, M. Jung, W. Sippl
Homology modeling and structure-based design of inhibitors for histone deacetylases from parasites
DPhG-Doktorandentagung 2014
10.-12.03.2014, Bayer HealthCare, Wuppertal
2013
T. Heimburg; J. Melesina; A. Walter, A.-T. Hauser, K. Schmidtkunz, M. Marek, C. Romier, R. Pierce, M. Schmidt, M. Jung, W. Sippl
Development of benzhydroxamic acids as small molecule inhibitors against smHDAC8 for the treatment of schistosomiasis
DPhG Annual Meeting 2013
09.10.-11.10.2013, Freiburg
J. Melesina, T. Heimburg, K. Wichapong, M. Schmidt, A. Hauser, C. Romier, R. Pierce, M. Jung, W. Sippl
Homology modeling of human parasites histone deacetylases
7th Summer School on Drug Design
15.-20.09.2013, Vienna, Austria
J. Melesina
Comparative analysis of histone deacetylase structures of human parasites
33rd European School of Medicinal Chemistry
07.-12.07.2013, Urbino