Research, Development And Industrial Processes
Components: Prof. E. Valoti, Dr. Valentina Straniero, Dr. Lorenzo Suigo (PhD student)
External collaborator: Dr. Andrea Casiraghi
The research group mainly focuses the work on the design and the synthesis of novel potentially bioactive molecules, on the scale-up to pilot-plant of synthetic steps, on the optimization of industrial processes, on the obtainment of chiral compounds, by using enantioselective synthesis, chiral resolution, or racemization, and on the characterization and the analysis of novel molecules.
The main research projects are the following:
1. FtsZ inhibitors as potential wide spectrum antimicrobials
Aiming at fighting the antimicrobial resistance, an innovative potential target is the bacterial cell division process and all the related crucial proteins. Among these proteins, FtsZ (Filamentous temperature Z) plays a pivotal role, and, in this context, our research group works on the development of inhibitors, having a 2,6-difluoro-benzamide moiety. This research is conducted in collaboration with the research group of Dr. Carlo Zanotto, at the Department of Medical Biotechnology and Translational Medicine of the University of Milan. Dr. Zanotto evaluates the molecules for their antimicrobial potencies, both on S. aureus and E. coli, together with the assessment of their cytotoxicity on human MRC-5 cells. Further long existing collaborations are with Dr. Victor Sebastián-Pérez working at Exscientia and with Dr. Martina Hrast at the University of Ljubljana. Recently, also Prof. William Margolin, Texas University, and Prof. Germán Rivas, CSIC in Madrid, joined the project. The aim of these recent collaborations is the complete evaluation of the mechanism of action of the most potent FtsZ inhibitors, by using microbiological and biochemical tools.
Main publications on this topic: Straniero, V. et al, Antibiotics (Basel, Switzerland) 2021, 10 (4), 442. DOI: 10.3390/antibiotics10040442; Straniero, V. et al, ChemMedChem 2020, 15 (2), 195–209. DOI: 10.1002/cmdc.201900537; Straniero, V. et al, Antibiotics (Basel, Switzerland) 2020, 9 (4), 160. DOI: 10.3390/antibiotics9040160; Straniero, V. et al, ChemMedChem 2017, 12 (16), 1303–1318. DOI: 10.1002/cmdc.201700201; Straniero, V. et al, European journal of medicinal chemistry 2016, 120, 227–243. DOI: 10.1016/j.ejmech.2016.03.068; Chiodini, G. et al, European journal of medicinal chemistry 2015, 89, 252–265. DOI: 10.1016/j.ejmech.2014.09.100.
ERC panels: LS1_13 Early translational research and drug design; LS3_1 Cell cycle, cell division and growth; LS6_6 Infectious diseases; LS6_9 Antimicrobials, antimicrobial resistance; PE5_18 Medicinal chemistry.
2. RnpA inhibitors as potential antimicrobial agents.
RnpA is a prokaryotic protein that recently arose as potential target while developing antimicrobial agents, due to its involvement in at least two important processes, which are essential for bacterial growth and division: mRNA degradation and ptRNA maturation. Recently, our research group developed a series of RnpA inhibitors, in collaboration with the research group of Dr. Carlo Zanotto, at the Department of Medical Biotechnology and Translational Medicine of the University of Milan, of Prof. Paul Dunman, at the University of Rochester, USA, and of Dr. Sebastián-Pérez at Exscientia.
Main publication on this topic: Suigo, L. et al, Antibiotics (Basel, Switzerland) 2021, 10 (4), 438. DOI: 10.3390/antibiotics10040438.
ERC panels: LS1_13 Early translational research and drug design; LS6_6 Infectious diseases; LS6_9 Antimicrobials, antimicrobial resistance; PE5_18 Medicinal chemistry.
3. α-synuclein / Synapsin III modulators as disease-modifying agents for the treatment of Parkinson’s disease.
Parkinson’s disease (PD) is a well-known and common disease in the word today, and its actual therapy has several limits. In this topic and in collaboration with the research groups of Prof. Arianna Bellucci and Prof. Alessandra Gianoncelli at the Department of Molecular and Translational Medicine at the University of Brescia, our research group developed a series of methylphenidate (MPH) analogues, able to positively modify the interaction between α-synuclein and Synapsin III, two pivotal proteins in PD. Indeed, the modulation of this protein complex can affect not only the vesicle trafficking, but also α-synuclein pathological aggregates, thus reducing Lewy bodies. These cytoplasmatic inclusions are diagnostic of the disease progression and severity and were proved to be formed by the complex of both the two proteins. To verify and validate the α-synuclein/ Synapsin III complex as the target of this class of compounds, we started a collaboration with the group of Prof. Amy Newman at NIH in Baltimore, USA.
Main publications on this topic: Casiraghi, A. et al, ChemMedChem 2020, 15 (14), 1330–1337. DOI: 10.1002/cmdc.202000128; Faustini, G. et al, Neurobiology of disease 2020, 138, 104789. DOI: 10.1016/j.nbd.2020.104789, PCT/EP2021/071717.
ERC panels: LS1_13 Early translational research and drug design; LS5_2 Glial cells and neuronal-glial communication; LS5_11 Neurological and neurodegenerative disorders; PE5_18 Medicinal chemistry.
4. Farnesyl Transferase inhibitors as antiproliferative agents.
Farnesyl transferase (Ftase) is a human enzyme indirectly involved in cellular proliferation, and thus abundantly studied for its implication in tumors, atherosclerosis, and protozoal infections. In the recent years, Ftase inhibitors were further considered and evaluated also for their implication in extracellular vesicles regulation, which influences the formation of tumoral metastasis. In this research field, our group synthesized many peptidomimetics, as Ftaseinhibitors, and a novel deuterated lysobisphosphatidic acid, as internal standard for lipidomic analysis. This research is performed in collaboration with the groups of Prof. Alberto Corsini at the Department of Pharmacological and Biomolecular Sciences and of Prof. Alessandra Puglisi at the Department of Chemistry, both working at the University of Milan.
Main publications on this topic: Straniero, V. et al, Bioorganic & medicinal chemistry letters 2014, 24 (13), 2924–2927. DOI: 10.1016/j.bmcl.2014.04.078; Bolchi, C. et al, Bioorganic & medicinal chemistry letters 2011, 21 (18), 5408–5412. DOI: 10.1016/j.bmcl.2011.07.003.
ERC panels: LS1_13 Early translational research and drug design; LS3_5 Cell signalling and signal transduction, exosome biology; LS4_12 Cancer; PE5_18 Medicinal chemistry.
5. Stereotechnologies on bioactive molecules
While working on the synthesis of several molecules, abundant is the number of compounds having one or more chiral centres, thus having different biological activities.
Is thus important to consider and study the preparation of single enantiomers, by enantio- or stereo- selective synthesis, as well as the resolution of racemic mixtures. Sometimes the study of the racemization of the distomer is required, especially for industrial processes. The evaluation of a single enantiomer, or of enantiomeric and diastereomeric systems, is possible by using different analytical techniques (spectroscopy, thermal analysis, electrophoresis, diffractometry, chromatography), and only after having a solid experience, both theoretical and practical.
Main publications on this topic: Straniero, V. et al, Chirality 2018, 30 (7), 943–950. DOI: 10.1002/chir.22968.; Casiraghi, A. et al The Journal of organic chemistry 2018, 83 (21), 13217–13227. DOI: 10.1021/acs.joc.8b02012.
ERC panels: LS1_13 Early translational research and drug design; PE5_17 Organic chemistry.