Since 2005 I am a CNR researcher working at the Institute of Biophysics. I work on the relationship between structure and function of proteins involved in different human diseases, using various experimental and computational techniques. In particular, I work in expression and purification of recombinant proteins, biophysical and biochemical characterization of purified proteins, production of protein crystals, structural analysis with X-ray crystallography, SAXS and electron microscopy. In addition, I work in in silico docking for the identification of inhibitors to be developed as new drugs and in molecular dynamics simulations.
Education and Training
1998-2002, PhD in Physics at the University of Genoa.
Title of PhD Thesis: "X-ray diffraction and molecular dynamics studies on truncated hemoglobin-N from Mycobacterium tuberculosis".
Tutors: Prof. M. Bolognesi and Prof A. Desideri.
1997-1998, Experimental thesis in Physics, University of Rome "La Sapienza". Vote: 110/110.
Title of the Experimental Thesis: "On the scattering mechanism of electrons interacting with surfaces in specular reflection geometry".
Tutor: Prof. G. Stefani.
October 1996 - May 1998 undergraduate research experience in experimental surface physics (with Prof. G. Stefani, "Roma 3" University, Rome).
June - December 1998, INFM (National Institute of Physics of Matter) fellowship, University "Roma Tre".
July 1999 - April 2005, research experience in the protein crystallography group of Prof. Martino Bolognesi (Advanced Biotechnology Center, Genoa).
March - May 2003 I have been working in the microbiology group of Prof. Paolo Visca in Spallanzani Hospital (Rome).
April 2005 - February 2009 I had a temporary position as researcher at CNR c/o University of Milano, Dep. of Biomolecular Science and Biotechnology.
February 2009 - Researcher at CNR - Biophysics Institute - Milano section.
Main Research Interests
After the initial experiences in matter physics and electron-surface interaction (Ruocco et al., 1999), my early researches were focused on the structure of a new class of bacterial proteins called truncated hemoglobins (TrHb; main publications: Milani et al., 2001; Milani et al., 2003; Milani et al., 2004).
The interest for bacterial proteins proceeded with the study of a two-component bacterial system in a quasi-active conformation (Milani et al., 2005) and, more recently, in the study of essential bacterial proteins to find new antibiotics (Uruburu et al., submitted).
Afterwards, I was involved in the study of the structure of several enzymes from RNA viruses (mostly flaviviruses) to better understand the activity of essential viral proteins like methyltransferase (Milani et al., 2009), helicase (Mastrangelo et al., 2007) and polymerase (Milani et al., 2009; Mastrangelo et al., & Milani, 2012). The structures of such proteins often provided useful information for the identification of potential binding sites for inhibitors (by in silico docking), characterized by binding experiments, point mutations and co-crystallization experiments. Among other inhibitors, I was able to identify the drug ivermectin (currently in clinical use as antiparasitic drug) as a potent inhibitor of flavivirus helicases (Mastrangelo et al., & Milani, 2012). The new ivermectin function is now under clinical trial (https://clinicaltrials.gov/ct2/show/NCT02045069).
My interest in protein with prosthetic groups was addressed to different flavoproteins involved in human diseases (Milani et al., 2007; Milani et al., 2011).
Another broad research interest is associated to the study of human proteins regulating cell apoptosis and in particular I participated to the structure-based optimization of small molecules (called SMAC mimetics) that are being developed as anticancer compounds (Cossu et al., 2009; Mastrangelo et al., & Milani 2015).
Recently, I am involved in the study of different calcium binding proteins responsible of human genetic diseases like gelsolin amyloidosis and cone dystrophy (Boni et al., 2016). Even in this case understanding the protein structure and dynamics can help in unraveling the molecular basis of the diseases. The identification of new strategies to restore the healthy behavior of these proteins is the main objective of my work.
2003-05, Adj. Prof. of Biochemical Physics (Dep. of Physics, University of Genoa, Italy).
2006-2014, Adj. Prof. of Biophysics (Dept. of Physics, University of Milan).
2007, C. Scolastico, L. Manzoni, P. Seneci, L. Belvisi, D. Delia, M. Bolognesi, E. Mastrangelo, M. Milani, I. Motto, C. Drago (2007). EPO 7021843. "New SMAC mimetic compounds as apoptosis inducers".
2011, Milani, Mastrangelo, Bolognesi et al. "Avermectins and milbemycins for the treatment of flavivirus infections" (WO2011051159 (A1)). Now in clinical trial: (https://clinicaltrials.gov/ct2/show/NCT02045069)
2012 PCT/IB2012/000297 deposited 20/02/2012: "New homo- and heterodimeric SMAC mimetic compounds as apoptosis inducers".
PLOS one; Journal of Nanoparticle Research, Journal of Virological Methods, Antiviral Research, Scientific Reports; BBA General Subjects.
Editorial board membership: Antiviral Chemistry and Chemotherapy; Journal of Antimicrobial Agents and Chemotherapy.
from 1999 to 2018, I am coauthor of 73 papers in peer-reviewed international journals. Total citations: 2605, H index 31.
Main awarded grants
2012 - 2013 Grant from 60 Pharmaceuticals, LLC "Ivermectin-mediated dengue virus inhibition".
Role: Principal Investigator.
2013 - 2016 Italian Projects PRIN: NOXSS (X-ray Single Shots of Nano Objects): structural determination of nano objects using the X-ray pulses from the European Free Electron Laser sources.
Role: Partner Coordinator.
2016 - 2019 grant Telethon: Cone dystrophies and retinal degeneration from protein structures to biological networks. Toward the design of therapeutic molecules.
Role: Partner Coordinator.
2018 - 2019 grant Instruct (https://www.structuralbiology.eu/) "Structural analysis of the interaction between retinal guanylyl cyclase 1 (GC1) and guanylate cyclase activating protein 1 (GCAP1)".
2007 August, invited speaker ECM-24, Marrakech. "Structure of flaviviral enzymes: helicase and methyltransferase".
2008 November, invited speaker at 7th ICAV, Beijing. Cina. "Structural based inhibition of flavivirus replication enzymes: Helicase and Methyltransferase".
2011, June, Villa Vigoni workshop in Cell death. invited speaker, "IAP: structure-based inhibition".
2011, Biophysical Society Meeting, Baltimore: "Flaviviral helicases: structure, function, inhibition and dynamics".
2012 Biophysical Society Meeting, San Diego: "Structure based inhibition of the calicivirus RdRp"
2012 25th ICAR- Sapporo, Japan, "Structure-based inhibition of norovirus RNA-dependent RNA-polymerases".
2013 26th ICAR-San Francisco, "Structure of norovirus RNA-dependent RNA-polymerase in complex with three naphthalene derivates inhibitors".
2015, 28th ICAR-Rome, "Targeting the flavivirus polymerase: a new class of non-nucleoside inhibitors mimicking the stacking interaction of two RNA bases".
2016, 29th ICAR- San Diego, "Targeting RNA dependent RNA polymerase: the discovery of a new class of potent compounds against flaviviruses".
2017, Drug Discovery and Therapy World Congress 2017, Boston, invited speaker: "The difficult path toward the knowledge: an ongoing story on new class of Dengue virus inhibitors".
Member of the doctorate school in Molecular Biology of the Cell. Supervision of graduate and PhD students in Physics and in Biology, University of Milan (Italy)