Bolognesi's MedChem Lab (BOMedChem Lab). Coordinator: Bolognesi

Fig. 1: Schematic representation of the PROTAC mechanism of action

Research Themes

Development of chimeric small molecules as multi-target-directed ligands (MTDLs) to contrast the multifactorial nature of neurodegenerative diseases (e.g., Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, ALS) or as bimodal derivatives for simultaneous therapy and fluorescence imaging in prion disease.

An innovative class of chimeric molecule that have recently attracted our attention is that of degraders. We particular focus on two types of such heterobifunctional small molecules, i.e., the PRoteolysis TArgeting Chimeras (PROTACs) and RIBOnuclease-TArgeting Chimera (RIBOTACs).

PROTACs feature a ligand for the protein of interest (POI), and a ligand that recruits an E3 ubiquitin ligase connected via a suitable linker; similarly, RIBOTACs are composed of an RNA of interest (ROI)-binding compound conjugated to a second small molecule that recruits and locally activates RNase L. The formation of a ternary complex between the POI (or ROI) and the E3 ligase (or RNase), provoke target degradation. As such, the use of binary degraders is a revolutionary therapeutic modality, which is driving a radical rethink of small molecule-based drug discovery. We have applied this new modality to infections by Leishmania and by Flavivirus (like West Nile Virus, Zika virus and Dengue virus). In addition, we have recently pursued PROTAC-induced glycogen synthase kinase 3β degradation as a potential therapeutic strategy for Alzheimer’s Disease (Fig.1).

Fig. 2: Sustainable production of bioactive molecules from CNSL food waste

Our focus on sustainable drug discovery includes the use of renewable resources and the concomitant application of green strategies for drug development, following the principles of benign-by-design. Currently, we are using cashew nut shell liquid (CNSL), a byproduct of cashew nut manufacturing, to generate novel bioactive compounds for the neurodegenerative and antiparasitic drug discovery fields (Fig.2).

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Lab Members

Maria Laura Bolognesi, Full Professor

Elisa Uliassi, Senior Assistant Professor

Eleonora Diamanti,  Junior Assistant Professor

Lorna Piazzi, Research Fellow (Project Manager of TClock4AD - Targeting Circadian Clock Dysfunction in Alzheimer’s Disease) 

Bianca Martinengo ,  PhD Student

Viviana Mitarotonda, PhD Student (in co-tutoring with Prof. Bartolini) 

Federico Sdei, PhD Student

Ela Radosevic, PhD Student

Dionysis Kampasis, PhD Student

Filippo Piazza, PhD Student

Aurora Gaza, PhD Student

Alberto Pettinari, PhD Student

Job Openings or Internship Projects

Experimental activities aimed at carrying out the degree thesis in Pharmaceutical Chemistry (max 5 per year) https://www.unibo.it/sitoweb/marialaura.bolognesi/didattica?tab=tesi.

Furthermore, it is possible to do Erasmus exchanges and theses abroad in collaboration with various international groups (max 5 per year) https://www.unibo.it/sitoweb/marialaura.bolognesi/didattica?tab=accordi

Main Publications

• Exertier, C., Salerno, A., Antonelli, L., Fiorillo, A., Ocello, R., Seghetti, F., Caciolla, J., Uliassi, E., Masetti, M., Fiorentino, E., Orsini, S., Di Muccio, T., Ilari, A. and Bolognesi M. L. (2024). “Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis” Med. Chem.67: 402-419. https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.3c01439
• Pasieka, A., Diamanti, E., Uliassi, E. and Bolognesi, M. L. (2023) “Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?” ChemMedChem 18:1-17 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300422.
• Salerno, A., Seghetti, F., Caciolla, J., Uliassi, E., Testi, E., Guardigni, M., Roberti, M., Milelli, A., and Bolognesi M. L. (2022). “Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One” Med. Chem. 65: 9507-9530. https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.2c00302 
• Espro, C., Paone, E., Mauriello, F., Gotti, R., Uliassi, E., Bolognesi, M. L., Rodríguez-Padrón, D. and Luque, R. (2021) “Sustainable production of pharmaceutical, nutraceutical and bioactive compounds from biomass and waste” Chem. Soc. Rev., 50, 11191-11207. https://pubs.rsc.org/en/content/articlelanding/2021/cs/d1cs00524c
• Rossi, M., Freschi, M., Nascente, L. N., Salerno, A., Teixeira, S. M. V., Nachon, F., Chantegreil, F., Soukup, O., Prchal, L., Malaguti, M., Bergamini, C., Bartolini, M., Angeloni, C., Hrelia, S., Luiz Antonio Soares Romeiro, and Bolognesi, M. L. (2021) “Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer’s Disease” . J. Med. Chem. 64, 4972-4990. https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.1c00048