Research Research topics

Research topics

Design, synthesis and evaluation of biologically-active molecules with the aim of deriving structure-activity relationships in order to optimize both potency and selectivity in the interaction with the target macromolecules.

Prof. Maria Novella Romanelli, Prof. Elisabetta Teodori

Specifically, studies are related to:

• Molecules able to revert cancer cell resistance by inhibiting at the same time the efflux pumps responsible for the multidrug resistance (MDR) and carbonic anhydrase XII. Both membrane proteins are overexpressed in certain cancer cells that have developed resistance to chemotherapy.
• Molecules able to fight the infections carried by multidrug resistant Gram-negative bacteria acting as i) inhibitors of the RND efflux pumps responsible for the increase of drug extrusion toward the extracellular environment, ii) inhibitors of metallo beta-lactamase, responsible for the inactivation of beta-lactam anitibiotics, iii) inhibitors of bacterial biofilm formation, responsible for the persistence of infections after antibiotic therapy.
• Molecules able to block hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, a family of membrane proteins which controls cardiac and neuronal firing. Isoform-selective inhibitors are potentially useful to control neuropathic pain, epilepsy, heart rhythm and angina.

Molecules able to modulate human carbonic anhydrase isoforms. Selective inhibitors may be useful to manage pain, glaucoma and as anticancer drugs. Selective activators may be useful as tools to understand the physio pathological role of so far less studied carbonic anhydrase isoforms.

Design and synthesis of small molecules as pharmacological tools and potential therapeutics

Prof. Vittoria Colotta, Prof. Daniela Catarzi, and Prof. Flavia Varano

The research activity of the medicinal chemistry team focuses on the synthesis and structural characterization of new small molecules designed to target biological proteins involved in high social impact pathologies, and to identify new therapeutic approaches.

In particular, attention is directed towards the development of adenosine receptor ligands, carbonic anhydrase modulators, inhibitors of casein kinase 1δ and CD73, which represent possible new therapeutic agents for the treatment of cancer and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis.

A part of the research is devoted to the design and synthesis of multitarget molecules to explore their potential as innovative polypharmacological agents for multifactorial pathologies. The interdisciplinary approach is the driving force of the team activities, which will be closely coordinated with those of other research groups performing the biological and pharmacological characterization of the target compounds and their in silico structural optimization. The team also experiments with the implementation of green strategies for the synthesis and purification of the compounds that are the subjects of the research topics.

Design and synthesis of biologically active molecules

Prof. Claudiu.T. Supuran, Prof. Paola Gratteri, Dr. Alessio Nocentini, Dr. Alessandro Bonardi

The research group activity is mainly directed to:

- Prof. P. Gratteri: her research interests are directed to the development and application of bioinformatics and computational procedures applied to the study and evaluation of the mechanism underlying target/ligand recognition processes. The computational approaches mainly used, of the structure-based and ligand-based type, involve ▪ molecular docking; ▪ dynamic simulations (MDs); ▪ statistical mechanic for the analysis of thermodynamical properties of biological molecules. ▪ ADMET property predictions, ▪ mixed QM/MM methods; ▪ multivariate analysis. Her research contributions mainly focused on the targets ▪ DNA, both in the double stranded (ds) and non-canonical (i.e. G-quadruplex) conformations, and ▪ human and bacterial carbonic anhydrases (CAs)

Prof. Gratteri is the author of numerous publications on high impact international journals (https://pubmed.ncbi.nlm.nih.gov/?term=Gratteri+P+&sort=date&show_snippets=off; https://www.scopus.com/authid/detail.uri?authorId=6701616951)

- Prof. C.T. Supuran: his research interests include enzyme inhibitors and activators; carbonic anhydrases; matrix metalloproteinases and bacterial zinc proteases; cysteine proteases (SARS CoV-2 and related enzymes); tyrosinase; epoxide hydrolase cyclooxygenase; antiglaucoma drugs; antiobesity agents; antitumor drugs; antiinfectives for the management of drug resistant pathogens (antibacterials, antifungals, antiprotozoan agents); drugs for the management of neuropathic pain.

His research contributions mainly focused on the targets ▪ human and bacterial carbonic anhydrases (CAs)

Prof. Supuran is the author of numerous publications on high impact international journals (https://pubmed.ncbi.nlm.nih.gov/?term=Supuran+&show_snippets=off; https://www.scopus.com/authid/detail.uri?authorId=7102904152)

Drug design and development of new enzymatic modulators

Prof. Fabrizio Carta

The scientific activities are essentially focused within the Pharmaceutical and Nutraceutical Chemistry and specifically on those scientific disciplines related to Drug Discovery and Development (DDD). The studies include: in silico design, multi-step organic and/or organometallic synthesis, chemical/physical characterization and in vitro kinetic profiling of compounds with potential application/development for human and/or veterinary pharmaceutical-nutraceutical needs. Structural characterization and activity studies are also carried out on enzymes of relevance within the medical field and involved in inflammatory, tumor, neuronal and infectious diseases.

PeptLab - Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology

Prof. Paolo Rovero

PeptLab is a multidisciplinary research unit with a strong know-how in the field of peptide science (design, synthesis, and molecular characterization of peptides, both at the biological and structural level). The following project, better described on the Laboratory homepage (www.peptlab.unifi.it), are currently ongoing:

• Bioactive peptides for pharmaceutical and cosmeceutical applications.
• Innovative methodologies in peptide synthesis and modification.
• Peptides and sustainability: new approaches and applications to reduce impact on health.
• Peptide-based diagnostics in immune mediated diseases.
• Surface plasmon resonance for label-free analysis of biomolecular interactions.

Food Chemistry

Prof. Nadia Mulinacci, Prof. Marzia Innocenti

The research group deals with the development of extraction methods for the determination of secondary bioactive metabolites mainly from different parts (fruits, leaves, flowers, seeds, bark, tubers etc) of edible plants, medicinal plants and agri-food by-products. Among the activities there is also the application of chromatographic techniques (HPLC coupled to UV-Vis detectors or DAD), and combined MS spectrometry techniques (HPLC/API MS, MS/MS) and NMR analysis for the structural characterization of natural compounds present in plant extracts. One of the typical activities is to develop multitarget chromatographic methods for the quality control of plant extracts and extracts for food use predominantly containing phenolic compounds (phenylpropanoids, flavonoids, secoiridoids, stilbenoids, tannins, procyanidins), alkaloids and saponins.

Current research is listed below:

• Studies on the chemical composition and bioactivity of the secondary metabolites produced by Olea europaea L.: in particular, phenolic compounds in fruits, leaves, EVOO and pressing by-products, and headspace profiles (HS-SPME-GC- MS) of the volatile compounds of virgin olive oils.

• Studies on starch and resistant starch, phenols, sterylferulates in minor cereals (e.g. millet)

• Studies on coffee as a beverage and as by-products aimed at the determination of alkaloids and chlorogenic acids.

• Studies on the chemical composition and bioactivity of pomegranate fruit extracts (juice, peels, and fermented peels)

• Extraction and analysis of natural polysaccharides (extracts from pomegranate, algae, date fruits) and evaluation of their prebiotic properties.

• Production of plant extracts obtained from different matrices, quali-quantitatively characterized from a phytochemical point of view, to be used for in vitro and in vivo biological tests.

Pharmaceutical technology

Prof. Anna Rita Bilia, Prof. Maria Camilla Bergonzi, Prof. Francesca Maestrelli

The research is focused on the design, development, chemical-physical characterization and biopharmaceutical evaluation of innovative therapeutic systems. The improvement of bioavailability and technological features of drugs and natural products are obtained by using conventional and innovative drug delivery systems. The purpose of the studies is to increase the solubility and/or the chemical stability of various natural plant compounds or extracts to improve their effectiveness. Micro- and nanoformulations are designed and developed, in particular liposomes and vesicles, micelles, nanoparticles, micro and nanoemulsions, lipid carriers, inclusion complexes, solid dispersions, co-ground systems. Characterization of the colloidal carriers is performed by chromatographic methods (HPLC-DAD, HPLC-MS), Light Scattering (DLS, ELS) techniques, Transmission and scanning Electron Microscopy (TEM and SEM), Differential Scanning Calorimetry (DSC) solubility study and dissolution tests. Different media are used to check the stability of colloidal systems. In vitro parallel artificial membrane permeability (PAMPA) assay is applied to test the permeation of drug and drug-loaded formulation through different type of membrane that mimic physiological barriers (gastrointestinal, skin, blood-brain barrier). Caco-2 cells and hCMEC/D3 cells are available as model of the intestinal and the human blood brain barrier.

Application of advanced mass spectrometry (MS) techniques for the development of analytical methods to study molecules of biological and pharmaceutical interest

Prof. Gianluca Bartolucci

The potential of mass spectrometry techniques in pharmaceutical and biomedical fields are well documented. The high specificity, selectivity, and sensitivity of MS coupled with chromatography (gas and/or liquid mobile phases) affords the study of compounds either alone or in mixtures, as well as in complex matrices. In last decades’ MS was employed as selected analytical method for several different investigations such as stability of a drug in different matrices (buffers, plasma etc.), evaluation of possible biomarkers to characterize a disease or even determine the concentration of a specific compound (analyte) in a biological media. Prof. Bartolucci's MS laboratory is available to support other research groups by collaborating on the identification of new biological targets, quantitatively determining the analytes of interest and characterizing their chemical structures. The laboratory is equipped with various mass spectrometers covering both the analysis of volatile compounds (GC-MS) and polar compounds (HPLC-MS). Furthermore, the type of instrumentation available allows the application of complex experiments in MS or tandem mass spectrometry (MS/MS and MSⁿ) and accurate mass measurements (HRMS).

Cardiovascular pharmacology

Prof. Elisabetta Cerbai, Prof. Laura Sartiani, Prof. Raffaele Coppini

The research activity aims to study the pathophysiological mechanisms of cardiomyopathies to identify new therapeutic targets and novel pharmacological agents. Main research fields comprise acquired and congenital cardiovascular diseases with specific focus on the alterations occurring in the excitation-contraction properties of atria, ventricles or conduction system. The experimental activities are carried out using three different experimental approaches: ex-vivo, starting from surgical fragments of human atrial and ventricular tissues, or from animal models of rodents and zebrafishes; in vivo, using animal models of rodents and zebrafishes; in vitro, using short- and long-term cultures of cardiac myocytes or organoids obtained from rodent cell lines or differentiated from human pluripotent stem cells. This multilevel approach provides an integrated view of the cardiac functional complexity, ranging from the single cell to the intact tissue, where the different cell phenotypes interact into native networks, and ultimately to the organoids, where the different cell phenotypes are self-organized or are induced to organize by mimicking the relationships existing in the native tissues. The same experimental approaches are used to study the pharmacologically active substances (obtained by chemical synthesis and/or purification of nutraceuticals), which modulate the excitation-contraction function/dysfunction of cardiac cell/tissue, acting on multiple molecular targets, including ion channels/pumps, exchangers, receptor complexes and transcription factos. The experimental techniques used in the research are the most advanced for the study of cardiac excitation-contraction coupling (electrophysiology, optogenetics and live-imaging fluorescence), the associated molecular counterpart (gene/protein expression, screening of genetic variants, immuno-histo/cyto-chemistry), and the genome editing through plasmid and viral vectors.

Anticancer pharmacology

Dr. Stefania Nobili

The research concerns the study of cytotoxicity of new compounds with potential antitumor activity and molecular mechanisms of anticancer drug sensitivity/resistance in preclinical tumor models; translational studies of pharmacogenetics and pharmacogenomics aimed at the identification and validation of molecular determinants responsible for tumor drug resistance or toxicity in major solid and hematologic malignancies.

The study of these determinants, either as predictive biomarkers of response or as potential targets of action of anticancer drugs or as sites of modulation by agents enhancing the activity of anticancer drugs, can represent the basis for the development of more effective personalized anticancer therapies.

Such studies are conducted by cell and/or molecular biology techniques, on established tumor cell lines of human origin, sensitive or resistant (by intrinsic or acquired resistance) to anticancer drugs, in tumor explants or biological fluids from patients and in in vitro cell models derived from them.

Neuroinflammation and cellular senescence

Prof. Nicoletta Galeotti

The research activity is aimed at (i) studying the mechanisms underlying the development of neuroinflammation and cellular senescence in neurodegenerative pathologies associated with neuropathic pain, (ii) identification of new pathophysiological mechanisms, (iii) identification of potential targets for the preclinical development of innovative therapies. In vitro studies are conducted on glial and neuronal cell lines through which the etiological causes of some of the main neuropathies are reproduced. In vivo studies involve the use of animal models of both central and peripheral painful neurodegenerative pathologies such as multiple sclerosis, diabetic, alcoholic and trauma-induced neuropathy. The analysis of biological samples of nervous tissue allows the study of the processes of neuroinflammation, cellular senescence and the tissue accumulation of senescent cells in relation to the induction and progression of the pathology. The investigation into the development of therapeutic interventions involves the modulation of intracellular pathways involved in the onset of neuroinflammation and cellular senescence at the microglial level, such as RNA binding proteins, CB2 and TREM receptors, epigenetic modulators, and in pain perception at both central and peripheral levels. Potential innovative treatments include natural substances, new synthetic molecules and precision medicine interventions such as antisense strategies.

Pharmacology of pain

Prof. Carla Ghelardini, Prof. Lorenzo Di Cesare Mannelli

The research is focused on the study of the pathophysiological mechanisms of pain, the identification of new therapeutic targets and the preclinical development of pharmacologically active substances. Persistent somatic and visceral pain is analysed in its nociceptive, inflammatory, neuropathic and nociplastic components. In vitro, studies are conducted in neuronal and glial cell lines, organotipic cultures of spinal cord, and organoids. The development of new non-animal models is particularly taken care of through the creation of colon epithelial organoids, for the study of intestinal alterations associated with visceral hypersensitivity, and organoids of dorsal root ganglia (derived from human induced pluripotent stem cells) for the study of peripheral neuropathies. In vivo, algic pathologies such as osteoarthritis and rheumatoid arthritis, trauma- and chemotherapy-induced neuropathies as well as chronic intestinal diseases are studied. The therapeutic approach is based on the modulation of molecular pain mediators (such as VEGF-A receptor 1 or pannexin channel 1) or regulatory systems (such as the glymphatic system, an astrocyte-mediated transport mechanism that allows the cerebrospinal fluid influx from the perivascular space to the interstitial space of the cerebral parenchyma and, in output, the drainage of neurotoxic waste substances) or symbiotic relationships (such as intestinal bacterial flora through fecal microbiota transplantation). Small molecules obtained by chemical synthesis, biotechnological products and natural substances obtained from terrestrial and marine organisms are studied.

Experimental and translational toxicology unit

Prof. Cristina Luceri, Prof. Lisa Giovannelli, Dr. Elisabetta Bigagli

Clinical research: study of risk factors associated with the development of chronic-degenerative diseases such as tumors, metabolic and gastrointestinal diseases.

• Identification of biomarkers of susceptibility and response to therapy

-Identification of novel biochemical and epigenetic biomarkers for prognosis and for predicting therapeutic response or drug toxicity in adults and in pediatric patients.

-Identification of biochemical, genetic, and epigenetic biomarkers predictive of health risk, in particular for the onset cancer associated with lifestyle, diet or occupational exposure to toxicants in healthy volunteers and exposed workers.

The research projects are multidisciplinary and carried out in collaboration with clinicians (SODs of Gynecology, Gastroenterology, Abdominal Surgery, Otolaryngology, Diabetology and Clinical Nutrition at Careggi Hospital and with Meyer).  On biological samples (tissues and body fluids), omics analyses (miRNome and transcriptome) miRNAs measurements, analysis of nuclear DNA damage, proteins and markers for the evaluation of oxidative stress or inflammation, are carried out.

• Safety profile assessment of drugs in not for profit clinical trials

The research involves collection, evaluation and monitoring of adverse events, interaction with Regulatory Authorities and Ethics Committees, continuous reassessment of the risk-benefit profile (Assignment of pharmacovigilance manager and EMA qualifications for the transmission of SUSARs and the use of the XEVMPD database).

Preclinical research: pharmaco-toxicological evaluation of synthetic molecules and extracts of natural origin in terms of cellular toxicity, intestinal absorption according to EMA, ICH M9 guidelines, gastro-protective activity, modulation of inflammation, oxidative stress and definition of the mechanism of action.

The projects are carried out on cellular models such as Caco2 differentiated on trans-well, Episkin reconstructed epithelia, human keratinocytes, human dermal fibroblasts, murine macrophages and tumor cell lines.

Pharmacovigilance and pharmacoepidemiology

Prof. Alfredo Vannacci, Dr. Niccolò Lombardi, Dr. Giada Crescioli, Eng. Roberto Bonaiuti                                         

The research is based on an analytical, observational, and biostatistical approach aimed at acquiring the maximum number of scientifically and clinically relevant information regarding the benefit/risk profile of drugs, vaccines, and integrative medicine products used by the population in the real world (real-world evidence). Through highly profiled multidisciplinary expertise, advanced equipment, and facilities, pharmacological research activity in pre- and post-marketing surveillance develops particularly in the following areas: preclinical and clinical evaluation of pharmacodynamic and pharmacokinetic mechanisms in the development of adverse drug reactions and events following immunization; assessment of drug safety in the treated population, with particular attention to specific age groups (<18 and ≥65), conditions (e.g., pregnancy and breastfeeding, addictions, etc.), and operational areas particularly at risk (e.g., emergency department, medical toxicology, etc.); evaluation of efficacy and safety of integrative medicine products (phytovigilance and clinical phytotherapy); assessment of prescribing appropriateness of drugs and their consumption in clinical practice (pharmacoutilization).

Technological solutions for pharmacology and pharmacovigilance: the Scarab joint laboratory (Joint Laboratory of Technological Solutions for Clinical Pharmacology, Pharmacovigilance, and Bioinformatics) (Neurofarba Dep., Dynamedics, Spindox)  focuses on the design and development of computer applications in the healthcare sector, with a particular specialization towards pharmacology, pharmacovigilance, and pharmacoepidemiology.

Perinatal Pharmacology: the PeaRL Perinatal Research Laboratory, jointly established by the Neurofarba Department of the University of Florence and the CiaoLapo ETS Foundation, promotes basic, pre-clinical, epidemiological, and clinical research on mental and physical health in the perinatal period. The main focuses of the laboratory are: the conscious use of drugs during pregnancy and after birth, the management of issues related to misuse, abuse, or dependence on drugs and substances during pregnancy and breastfeeding, the effects of environmental pollutants, lifestyle and life events on the psychophysical well-being of women and couples and on child neurodevelopment, from preconception to the first thousand days of life.

Pediatric Rheumatology

Prof. Gabriele Simonini

The research activity develops in the field of chronic inflammatory diseases of childhood. Juvenile idiopathic arthritis, Kawasaki disease, uveitis, pediatric connective tissue diseases and auto-inflammatory syndromes are the main pathologies towards which the research areas are mainly dedicated.

Of note, the following projects are active in the various research areas:

• KAWASAKI syndrome: Identification of pathogenetic inflammatory mechanisms and bio-humoral markers of coronary involvement.
• AUTOINFLAMMATORY SYNDROMES: genotype-phenotype correlation and risk stratification of disease severity
• Childhood chronic non-infective uveitis: clinical, genetic and lacrimal markers for identification of predictive factors of biological therapy efficacy
• Pediatric connective tissue diseases: identification of factors predictive of disease outcome
• Pediatric scleroderma syndromes: outcome and response to therapy
• Behcet's syndrome: transcriptomic and genomic analysis of cohort for identification of distinctive factors compared to the adult phenotype
• Therapy with modulating biological activity drugs: identification of anti-drug auto-antibodies and clinical correlations of efficacy
• There are active and constant research collaborations with international centers and companies:

Pediatric Rheumatology International Trials Organization (PRINTO)

Childhood Arthritis and Rheumatology Research Alliance (CARRA)

Pediatric Rheumatology European Society (PReS)