Research at the MedChemLab focuses on the identification and characterization of new molecules to modulate targets and biological processes involved in neurodegeneration, tumors and bacterial resistance, with the aim of developing new therapeutic approaches. The inter-disciplinary approach is the driving force of the research activity, which entails the design, synthesis and analysis of new focused compound libraries, as well as the preparation and characterization of chiral compounds. The group also experiments the implementation of green strategies for the synthesis and purification of the compounds that are the subjects of the research topics. Over the years, the group has prepared more than 1000 molecules (both natural and synthetic compounds) with drug-like properties. The biological investigations are carried out with several national and international collaborations. Here below a brief description of the research topics is reported.
- New neuroprotective agents: agonists of the Sigma-1 receptor (S1R).
- New anticancer frontier
- Small molecules able to interfere with ELAV proteins
- Bacterial Quorum Sensing (QS) inhibitors as tools to counteract antimicrobials resistance
- Nature-Aided Drug Discovery
- New neuroprotective agents: agonists of the Sigma-1 receptor (S1R).
The S1R is involved in several physio-pathological functions of the central nervous system (CNS) and plays a key role in neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease and neuropathies. S1R modulators with agonist profile can serve both as pharmacological tools to investigate the molecular mechanisms underlying neurodegenerative diseases, and as promising neuroprotective agents to counteract them. On the other hand, S1R antagonists are being studied as potential analgesics for the treatment of neuropathic pain.
Among the wide series of S1R ligands developed so far by our team, compound (R)-RC33 (a selective S1R agonist, metabolically stable) is currently under optimization for ALS treatment and is being used to build molecular probes to study the interactions of S1R with other potential therapeutic targets. Concurrently, we have developed and patented a small library of selective S1R antagonists, from which compound PV-752 emerged for its high efficacy in two animal models of neuropathic pain. The group has also identified, for the first time, some S1R agonists able to modulate the activity of aquaporins (AQPs), which are membrane channels involved in water permeability and scavenging of reactive oxygen species
- Rossino, G.; Rui, M.; Linciano, P.; Rossi, D.; Boiocchi, M.; Peviani, M.; Poggio, E.; Curti, D.; Schepmann, D.; Wünsch, B.; González-Avendaño, M.; Vergara-Jaque, A.; Caballero, J.; Collina, S. Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization. J. Med. Chem. 2021, 64 (20), 14997–15016. https://doi.org/10.1021/acs.jmedchem.1c00886.
- Pellavio, G.; Rossino, G.; Gastaldi, G.; Rossi, D.; Linciano, P.; Collina, S.; Laforenza, U. Sigma-1 Receptor Agonists Acting on Aquaporin-Mediated H2O2 Permeability: New Tools for Counteracting Oxidative Stress. Int. J. Mol. Sci. 2021, 22 (18), 9790. https://doi.org/10.3390/ijms22189790.
- Rossino, G.; Rui, M.; Pozzetti, L.; Schepmann, D.; Wünsch, B.; Zampieri, D.; Pellavio, G.; Laforenza, U.; Rinaldi, S.; Colombo, G.; Morelli, L.; Linciano, P.; Rossi, D.; Collina, S. Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R). Int. J. Mol. Sci. 2020, 21 (20), 7708. https://doi.org/10.3390/ijms21207708.
2. New anticancer frontiers
Since chemotherapy remains the first-choice treatment for the majority of tumors, low selectivity and high toxicity against non-neoplastic tissues are the typical drawbacks. Therefore, the identification of new anticancer agents with few side-effects is still challenging. The driving force of this project is the identification of “druggable” proteins, focusing on modulation, selective or simultaneous, of sigma receptors, of proteasome and/or of fibroblast growth factor receptors (FGFR) are the target of our research. Each of these proteins is involved in different processes related to cell survival and proliferation, and they are therefore considered promising therapeutic targets in the fight against cancer. Particularly, we spent our efforts in identifying new anticancer agents with anti-proliferative and pro-apoptotic effects through a S1R antagonist and S2R agonist profile, such as RC-106. Moreover, a series of pan-SR ligands exhibited promising activity against aggressive tumors and they act through multiple mechanisms of action, including the inhibition of proteasome. Lastly, a new series of compounds with a promising activity against glioblastoma, multiple myeloma and pancreatic cancer is the subject of an international patent. Regarding proteasome, a rational design approach starting from a natural compound as proteasome inhibitors was applied and the SAR profile is currently being drawn. Contextually, we have identified ligands selective for the extracellular domains of FGFR, which could represent an additional weapon against neoplasms, since the FGF/FGFR pathway plays a key role in tumor progression and in drug resistance.
- Tesei, A.; Cortesi, M.; Bedeschi, M.; Marino, N.; Rossino, G.; Listro, R.; Rossi, D.; Linciano, P.; Collina, S. Repurposing the Antiplatelet Agent Ticlopidine to Counteract the Acute Phase of ER Stress Condition: An Opportunity for Fighting Coronavirus Infections and Cancer. Molecules 2022, 27, 4327. https://doi.org/10.3390/molecules27144327
- Listro R.; Stotani, S.; Rossino G.; Rui M.; Malacrida A.; Cavaletti G.; Cortesi M.; Arienti C.; Tesei A.; Rossi D.; Di Giacomo M.; Miloso M.; Collina S. Exploring the RC-106 chemical space: design and synthesis of novel (E)-1-(3-arylbut-2-en-1-yl)-4-(substituted) piperazine derivatives as potential anticancer agents, Frontiers in Chemistry 2020 8, 495. https://doi.org/10.3389/fchem.2020.00495
- A. Tesei, M. Cortesi, A. Zamagni, C. Arienti, S. Pignatta, M. Zanoni, M. Paolillo, D. Curti, M. Rui, D. Rossi and S. Collina Sigma Receptors as Endoplasmic Reticulum Stress “Gatekeepers” and their Modulators as Emerging New Weapons in the Fight Against Cancer. Front. Pharmacol., 10 July 2018 | https://doi.org/10.3389/fphar.2018.00711
3. Small molecules able to interfere with ELAV proteins.
ELAV proteins belong to the class of RNA-binding proteins (RBPs) which malfunction is associated with different pathologies, including neurodegeneration and cancer. Our team, exploiting a medicinal chemistry approach, is investigating in-depth the concept of druggability of complexes between mRNA and HuR, a protein of the ELAV family. Through docking studies, we examined the possible interactions of compounds already identified as inhibitors of HuR–RNA, thus hypothesizing the binding pocket. This served as the starting point for the design of novel specific ligands.
Thus, combining interaction studies based on NMR techniques and in silico investigations, different chemotypes are currently under investigation, and some important structural requirements for the HuR-ligand interaction have already been identified. On the basis of these results, new chemical entities are being designed and synthesized, some of which are already under evaluation.
- Ambrosio, F. A.; Coricello, A.; Costa, G.; Lupia, A.; Micaelli, M.; Marchesi, N.; Sala, F.; Pascale, A.; Rossi, D.; Vasile, F.; Alcaro, S.; Collina, S. Identification of Compounds Targeting HuD. Another Brick in the Wall of Neurodegenerative Disease Treatment. J. Med. Chem. 2021, 64 (14), 9989–10000. https://doi.org/10.1021/acs.jmedchem.1c00191.
- Volpe, S. D.; Listro, R.; Parafioriti, M.; Di Giacomo, M.; Rossi, D.; Ambrosio, F. A.; Costa, G.; Alcaro, S.; Ortuso, F.; Hirsch, A. K. H.; Vasile, F.; Collina, S. BOPC1 Enantiomers Preparation and HuR Interaction Study. From Molecular Modeling to a Curious DEEP-STD NMR Application. ACS Med. Chem. Lett. 2020, 11 (5), 883–888. https://doi.org/10.1021/acsmedchemlett.9b00659.
- Della Volpe, S.; Nasti, R.; Queirolo, M.; Unver, M. Y.; Jumde, V. K.; Dömling, A.; Vasile, F.; Potenza, D.; Ambrosio, F. A.; Costa, G.; Alcaro, S.; Zucal, C.; Provenzani, A.; Di Giacomo, M.; Rossi, D.; Hirsch, A. K. H.; Collina, S. Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies. ACS Med. Chem. Lett. 2019, 10 (4), 615–620. https://doi.org/10.1021/acsmedchemlett.8b00600.
4. Bacterial Quorum Sensing (QS) inhibitors as tools to counteract antimicrobials resistance.
An innovative strategy to counteract antimicrobial resistance (AMR) is to interfere with the biofilm formation and with QS signaling, the cell-to-cell mechanism that bacteria use to communicate, coordinate and act as a population. The bacterial kinase LsrK plays a key role in the QS process. Our team studies the druggability of LsrK, evaluating its potential as a new pharmacological target to develop novel drugs, to be used alone or in combination with current antimicrobials. To identify new potential and developable LsrK inhibitors, we combined virtual screening of an in-house library of plant secondary metabolites with a focused synthesis of small molecules. Selected compounds were tested against LsrK, and the analogue search conducted based on the positive hits led to the identification of low-micromolar LsrK inhibitors. The research, which is currently in its early phase, may lead to the identification of new antibacterial compounds with innovative modes of action.
- Linciano, P.; Cavalloro, V.; Martino, E.; Kirchmair, J.; Listro, R.; Rossi, D.; Collina, S. Tackling Antimicrobial Resistance with Small Molecules Targeting LsrK: Challenges and Opportunities. J Med Chem 2020, 63 (24), 15243–15257. https://doi.org/10.1021/acs.jmedchem.0c01282.
- Stotani, S.; Gatta, V.; Medarametla, P.; Padmanaban, M.; Karawajczyk, A.; Giordanetto, F.; Tammela, P.; Laitinen, T.; Poso, A.; Tzalis, D.; Collina, S. DPD-Inspired Discovery of Novel LsrK Kinase Inhibitors: An Opportunity To Fight Antimicrobial Resistance. J Med Chem 2019, 62 (5), 2720–2737. https://doi.org/10.1021/acs.jmedchem.9b00025.
5. Nature-aided drug discovery
This research topic is transverse to the others. Indeed, natural products play a major role in the discovery of valuable bioactive molecules. The extraction, characterization and biological evaluation of secondary metabolites can lead to the discovery of compounds endowed with high therapeutic potential. Our group investigates both local and non-local plants selected via literature survey, computational models or ethnobotanical evidence. Particularly, natural matrices are extracted via conventional (maceration) and innovative (microwave and ultrasound assisted extraction) methods and fractionated with a bio-guided fractionation approach. Following this approach, during the years we have reached several successful goals like, citing few examples, the isolation of an anti leishmanial molecule from Eremurus persicus, the identification of wound healing properties of Marrubium vulgare extract or of the TNF-α blocker effect of naringenin-loaded sericin. More recently, we are now studying metabolites with neuroprotective, anti-inflammatory and anticancer activities, as well as compounds able to interfere with ELAV-RNA complex (research topic 3) and inhibitors of LsrK (research topic 4).
- Rossi, D., Ahmed, K.M., Gaggeri, R., Volpe, S.D., Maggi, L., Mazzeo, G., Longhi, G., Abbate, S., Corana, F., Martino, E., Machado, M., Varandas, R., Do Céu Sousa, M., Collina, S. (R)-(-)-Aloesaponol III 8-methyl ether from eremurus persicus: A novel compound against leishmaniosis. Molecules 2017, 22 (4), 519. https://doi.org/10.3390/molecules22040519
- Cavalloro, V., Marrubini, G., Stabile, R.; Rossi, D., Linciano, P., Gheza, G., Assini, S., Martino, E., Collina S. Microwave-Assisted Extraction and HPLC-UV-CD Determination of (S)-usnic Acid in Cladonia foliacea. Molecules 2021; 26(2): 455. https://doi.org/10.3390/molecules26020455
- Malacrida, A., Cavalloro, V. ,Martino, E., Costa, G., Ambrosio, F.A., Alcaro, S., Rigolio, R., Cassetti, A., Miloso, M., Collina S. Anti-Multiple Myeloma Potential of Secondary Metabolites from Hibiscus sabdariffa—Part 2. (2021) Molecules 26: 6596. https://doi.org/10.3390/molecules26216596