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) (https://www.sciencedirect.com/science/article/abs/pii/S0223523425006336), 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) (https://doi.org/10.1021/acs.jmedchem.5c01617).

For additional information, visit our website.

Lab Members

Maria Laura Bolognesi, Full Professor

Andrea Milelli, Associate Professor

Elisa Uliassi, Senior Assistant Professor

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

Bianca Martinengo,  Visiting graduate

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

Federico Sdei, PhD Student

Ela Radosevic, PhD Student

Dionysis Kampasis, PhD Student

Alexandros Zantis, Ph.D Student

Filippo Piazza, PhD Student

Aurora Gaza, PhD Student

Alberto Pettinari, PhD Student

Patricia Garcia Lopez Izabella, Visiting PhD Student

Job Openings or Internship Projects

For experimental activities related to the Pharmaceutical Chemistry degree thesis, students are invited to consult the pages of Prof. Bolognesi and Prof. Milelli.

Erasmus+ exchanges and thesis projects abroad are also available, in collaboration with several international research groups. Further information can be found on the following pages: Erasmus+ Agreements – Prof. Bolognesi and Erasmus+ Agreements – Prof. Milelli

Main Publications

• Martinengo B, Baldassarri C, Ilbeigi K, Alkhalaf HE, Sarode A, Elmahallawy EK, Kwon BR, Agyei AS, Abdimanova A, de Almeida Fiuza LF, Azevedo R, da Conceição K, Meuser Batista M, Borges EN, Freitas E Silva KS, Cardoso ÉJS, Monteiro NC, Nunes Lemes LF, Soares Romeiro LA, Alonso A, Soeiro MNC, Caljon G, Brooks BW, De Koning HP, Bolognesi ML. Sustainable Antiparasitic Agents from an Agro-Industrial Waste: Mitochondria-Targeting Cashew Nutshell Liquid-Derived Phosphonium and Ammonium Salts. J Med Chem. 2025 Sep 25;68(18):19438-19462. doi: 10.1021/acs.jmedchem.5c01617
• Pinheiro PSM, de Chirico F, Loi M, Trazzi S, Ciani E, Rodrigues DA, Alves MA, Lima LM, Milelli A, Monti B, Manssour Fraga CA, Bolognesi ML. Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease. Eur J Med Chem. 2025 Oct 15;296:117868. doi: 10.1016/j.ejmech.2025.117868.
• 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
• Martinengo B, Diamanti E, Uliassi E, Bolognesi ML. Harnessing the 12 Green Chemistry Principles for Sustainable Antiparasitic Drugs: Toward the One Health Approach. ACS Infect Dis. 2024 Jun 14;10(6):1856-1870. doi: 10.1021/acsinfecdis.4c00172.
• Guardigni M, Pruccoli L, Santini A, Simone A, Bersani M, Spyrakis F, Frabetti F, Uliassi E, Andrisano V, Pagliarani B, Fernández-Gómez P, Palomo V, Bolognesi ML, Tarozzi A, Milelli A. PROTAC-Induced Glycogen Synthase Kinase 3β Degradation as a Potential Therapeutic Strategy for Alzheimer's Disease. ACS Chem Neurosci. 2023 Jun 7;14(11):1963-1970. doi: 10.1021/acschemneuro.3c00096