Research

Research in the MedChemLab focuses on medicinal chemistry. Our main areas of work are in structure-based drug design, in the study methodologies for the preparation of homochiral bioactive compounds. Here below a brief description of the research lines are reported.

  1. Sigma1 receptor agonists potentially active against neurodegenerative diseases
  2. Pan -Sigma receptor modulators: a new anticancer frontier
  3. RNA Binding Proteins (RBPs) as innovative targets. Toward the discovery of ELAV-RNA interacting compounds
  4. Nature-aided- drug discovery

1.Sigma1 receptor agonists, as neuroprotective agents, potentially active against neurodegenerative diseases

Sigma-1 receptors (S1Rs) are involved in several physio-pathological functions of the CNS, including neuroplasticity and neuroprotection. Accumulating evidences suggest that S1R agonists may be of great therapeutic interest as novel pharmacological tools to understand the molecular mechanisms underlying neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS), Multiple sclerosis (MS), Alzheimer Disease and to counteract them. However, there is urgent need for novel S1R ligands with optimal pharmacological and pharmacokinetic profile, with the potential for development as drug candidates for human use. Our team developed a small library of S1R ligands with optimal affinity for the receptor and identified RRC33 as a new selective and metabolically stable S1R agonist, characterized by an excellent CNS distribution (PK in vivo studies).   

  1. Rui, M., Rossino, G., Coniglio, S., Monteleone, S., Scutieri, A., Malacrida, A., Rossi, D., Catenacci, L., Sorrenti, M., Paolillo, M., Curti, D., Venturini, L., Schepmann, D., Wünsch, B., Liedl, K.R., Cavaletti G., Pace, V., Urban, E., Collina, S. Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents. 2018, European Journal of Medicinal Chemistry, 158, pp. 353-370
  2. Marra, A., Rossi, D., Pignataro, L., Bigogno, C., Canta, A., Oggioni, N., Malacrida, A., Corbo, M., Cavaletti, G., Peviani, M., Curti, D., Dondio, G., Collina, S. Towards the identification of neuroprotective agents. G-scale synthesis, pharmacokinetic evaluation and CNS distribution of (R)-RC-33, a promising sigma1 receptor agonist. 2016 Future Medicinal Chemistry, 8, pp. 287-295.
  3. Peviani, M., Salvaneschi, E., Bontempi, L., Petese, A., Manzo, A., Rossi, D., Salmona, M., Collina, S., Bigini, P., Curti, D. Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation, 2014, Neurobiology of Disease, 62, pp. 218-232.

2.  Pan -Sigma receptor modulators: a new anticancer frontier

Chemotherapy still remains the first-choice treatment for the majority of tumors. Nevertheless, low selectivity and high toxicity against non-neoplastic tissues are the major drawbacks of conventional chemotherapies. 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, as novel molecular targets for the treatment of cancer. In the discovery of novel antitumor agents, able to guarantee a result with poor side-effects, Sigma Receptor (SR) modulators are fit for purpose.  There are two subtypes of SRs – S1R and S2R – based on anatomical distribution, pharmacological and pathological activities. S1Rs are well known and several modulators have been identified so far. In detail, S1R agonists are proved to exert neuroprotective and neuroplastic effects whereas S1R antagonists give rise to beneficial activities against neuropathic pain and cancer. Conversely, S2Rs still present enigmatic aspects, both from a structural and a pharmacological point of view. However, experimental evidence shows the overexpression of this molecular target in cancer cells and the scientific community strongly supports the idea that S2R modulators may have anti-proliferative and pro-apoptotic effects. Accordingly, we spent our efforts in identifying new anticancer agents, acting via SR modulation. Specifically, the project aimed at discovering molecules able to target both SR subtypes (pan-SR), in order to define SRs as the new anticancer frontier. Among our compound library, we identified RC-106 as the most promising pan-SR antitumor molecule, in virtue of its cytotoxic properties towards a pool of cancer cell lines. The extraordinary results led us to pursue in this aim in fact other assays are in progress.

  1. 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
  2. Collina, S., Bignardi, E., Rui, M., Rossi, D., Gaggeri, R., Zamagni, A., Cortesi, M., Tesei, A. Are sigma modulators an effective opportunity for cancer treatment? A patent overview (1996-2016). 2017, Expert Opinion on Therapeutic Patents, 27 (5), pp. 565-578.
  3. Rossi, D., Rui, M., Di Giacomo, M., Schepmann, D., Wünsch, B., Monteleone, S., Liedl, K.R., Collina, S.* Gaining in pan-affinity towards sigma 1 and sigma 2 receptors. SAR studies on arylalkylamines. 2017, Bioorganic and Medicinal Chemistry, 25 (1), pp. 11-19.

3. RNA Binding Proteins (RBPs) as innovative targets. Toward the discovery of ELAV-RNA interacting compounds

The possibility to investigate gene expression at genome-wide levels by transcriptome, polysome or ribosome profiling, and quantitative proteomics has highlighted the intricacy and the importance of post-transcriptional control mechanisms in regulating protein expression levels. In this regard, it has been revealed how many RNA binding proteins (RBPs) orchestrate mRNA fate at crucial steps, including subcellular localization, stability and translation efficiency. Aberrant activity of RBPs, caused by inactivating mutations but also overexpression, is associated with human pathologies, including neurodegeneration and cancer. While the action of RBPs is highly combinatorial and much has to be learned about their sequence-specific interaction with RNA targets in vivo, several RBPs have been revealed to exhibit a prominent, potentially rate-limiting function, thus representing promising candidates for innovative drug therapies.

Our team studied the concept of druggability of HuR- and related ELAV-mRNA complexes. Sequence-alignment studies of the different ELAV proteins have shown that the first two RRM domains contain two highly conserved sequences, each of eight and six amino acids, appointed as RNP1 and RNP2 (Ribo Nucleo Protein), respectively. Specifically we had already studied and reported the importance of the four RNP sequences in binding and stabilizing a target transcript RNA by means of real-time quantitative PCR, molecular modeling and advanced NMR techniques (Saturation Transfer Difference, STD, and Diffusion-Ordered Spectroscopy, DOSY). Moreover, recently we analyzed the literature concerning the main findings on the ELAV–RNA complexes from a medicinal chemistry standpoint. Accordingly, through scouting docking studies we examined the possible interactions of the compounds already identified as inhibitors of HuR–RNA and evaluate the potential of computer-aided drug design (CADD) for use in future drug-discovery programs. Taken together, the gained docking results suggest that the studied compounds bind HuR in the same specific region. Thus, the hypothesized binding pocket may constitute the starting point for the design of specific ligands targeting this site through a structure-based drug design approach. In this project, new chemotypes were searched by a parallel strategy starting from the results obtained in our recent research (unpublished results) thanks to a combined NMR and in silico approaches.

To sum up, the results highlighted the main ligand structural features involved in HuR-ligand interaction, thus laying the foundation for both the synthesis of ad hoc designed NCEs (new chemical entities) and for future Structure Based Virtual Screening (SBVS) studies using different compound libraries.

  1. Vasile, F., Della Volpe, S., Ambrosio, F.A., Costa, G., Unver, M.Y., Zucal, C., Rossi, D., Martino, E., Provenzani, A., Hirsch, A.K.H., Alcaro, S., Potenza, D., Collina, S., Exploration of ligand binding modes towards the identification of compounds targeting HuR: a combined STD-NMR and Molecular Modelling approach. 2018, SciRep,. 8: n°13780.
  2. Nasti, R., Rossi, D., Amadio, M., Pascale, A., Unver, M.Y., Hirsch, A.K.H., Collina, S., Compounds Interfering with Embryonic Lethal Abnormal Vision (ELAV) Protein-RNA Complexes: An Avenue for Discovering New Drugs. 2017, Journal of Medicinal Chemistry, 60(20), pp. 8257-8267.
  3. Amadio, M., Pascale, A., Govoni, S., Laurini, E., Pricl, S., Gaggeri, R., Rossi, D., Collina, S.Identification of peptides with ELAV-like mRNA-stabilizing effect: an integrated in vitro/in silico approach. 2013 Chemical Biology and Drug Design, 81(6), pp. 707-714.

4. Nature-aided- drug discovery

  1. Pellavio, G., Rui, M., Caliogna, L., Martino, E., Gastaldi, G., Collina, S., Laforenza, U. Regulation of aquaporin functional properties mediated by the antioxidant effects of natural compounds. 2017 International Journal of Molecular Sciences, 18 (12), art. no. 2665.
  2. 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 (2017) Molecules, 22 (4).
  3. Amri, B., Martino, E., Vitulo, F., Corana, F., Ben-Kaâb, L.B., Rui, M., Rossi, D., Mori, M., Rossi, S., Collina, S.  Marrubium vulgare l. leave extract: Phytochemical composition, antioxidant and wound healing properties. 2017 Molecules, 22 (11), art. no. 1851.