Firenze, Italy

University of Florence
Firenze, Italy

The University of Florence is an Italian public research university located in Florence, Italy. It comprises 12 schools and has about 60,000 students enrolled. Wikipedia.

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Consortium for Science, Technology of Materials and University of Florence | Date: 2017-01-04

The present invention relates to molecules of formula (I) where R1 = -SO3H, -PO3H, -PO2(OH)2, -OPO2H2, -NHSO3H, -S (N=H)Me, SH, SR o guanidyl; R = C1-4 alkyl, phenyl or 5 or 6 membered aromatic nitrogen heterocycles; n = 1, 2, 3, 4 o 5; X = C=0, C(OH)H, C(OAIk)H, C=S, CH2; Alk = C1-6 alkyl linear, branched or cyclic, optionally hydroxylated or polyhydroxylated; their preparation and use as analgesics and in the treatment of pain induced by chemotherapies.

University of Florence and Azienda Ospedaliero Universitaria Careggi | Date: 2017-06-14

Here, we describe the detailed structure of an intact murine monoclonal anti-hERG1 molecule and the corresponding anti-hERG1 scFv antibody production, obtained after the isolation of the mAb anti-hERG1 VH and VL. Such scFv has the same 5 specificity of the correspondent whole antibody, and thus it is able to recognize the same anti-hERG1 protein, aberrantly expressed in tumours and other diseases

Chiti F.,University of Florence | Dobson C.M.,University of Cambridge
Annual Review of Biochemistry | Year: 2017

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions. © 2017 by Annual Reviews.

Amyloid diseases display the presence, in targeted tissues and organs, of fibrillar deposits of specific peptides or proteins. Increasing efforts are presently spent in investigating the structural features and the structure-toxicity relation of the soluble oligomeric precursors arising in the path of fibrillization as well as the importance of surfaces as triggers of protein misfolding and aggregation and as possible responsible for amyloid polymorphism. Presently, it is recognized that the unstable, heterogeneous pre-fibrillar aggregates are the main responsible for amyloid toxicity. Conversely, mature fibrils are considered stable, harmless reservoirs of toxic species, although direct fibril toxicity has been reported. Recent studies show that mature fibrils grown at various conditions can display different structural features, stabilities and tendency to disassemble with leak of toxic oligomers. Fibril polymorphism can result from protein aggregation at differing conditions populating misfolded monomers and oligomers with distinct conformational characteristics. Recent research has started to unravel oligomer structural and biophysical features and their relation to cytotoxicity. Increasing information supports the notion that oligomer-membrane interaction, disruption of membrane integrity and cell impairment results from both oligomer and membrane biophysical features; accordingly, the formation of the oligomer-membrane complex, often the first step of amyloid toxicity, can be the result of the interplay of these events. This view can help explaining the variable vulnerability of different cell types to the same amyloids and the lack of relation between amyloid load and severity of clinical symptoms; it also stresses the importance, for cell/tissue impairment, of the presence of fibrils conformers of reduced stability as a possible source of oligomers resulting from leakage possibly favored by the interaction with suitable macromolecular/lipid surfaces or by other environmental conditions. © 2012 Elsevier Ltd.

Supuran C.T.,University of Florence
Expert Opinion on Therapeutic Patents | Year: 2013

This issue of Expert Opinion on Therapeutic Patents is dedicated to carbonic anhydrase (CA, EC inhibitors (CAIs), a highly dynamic research topic in the last years. Several review articles and patent analyses on diuretics and antiglaucoma, antiepileptic, anti-obesity and anticancer agents belonging to the pharmacological class of the CAIs are presented, together with a review on bacterial, fungal and protozoan CAs and their inhibition as a novel means of designing anti-infectives. © 2013 Informa UK, Ltd.

Neri D.,ETH Zurich | Supuran C.T.,University of Florence
Nature Reviews Drug Discovery | Year: 2011

The high metabolic rate of tumours often leads to acidosis and hypoxia in poorly perfused regions. Tumour cells have thus evolved the ability to function in a more acidic environment than normal cells. Key pH regulators in tumour cells include: isoforms 2, 9 and 12 of carbonic anhydrase, isoforms of anion exchangers, Na +/HCO 3 co-transporters, Na +/H + exchangers, monocarboxylate transporters and the vacuolar ATPase. Both small molecules and antibodies targeting these pH regulators are currently at various stages of clinical development. These antitumour mechanisms are not exploited by the classical cancer drugs and therefore represent a new anticancer drug discovery strategy. © 2011 Macmillan Publishers Limited. All rights reserved.

Chiarugi A.,University of Florence
Trends in Pharmacological Sciences | Year: 2012

The exploitation of synthetic lethality in BRCA-deficient tumor carriers using potent inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP)-1 has led to an enthusiastic response among basic scientists, oncologists and pharmaceutical companies. However, accumulating evidence demonstrates that resistance to these drugs develops in tumors in both preclinical and clinical settings. Here, I focus on literature dealing with resistance to these drugs and discuss the molecular mechanisms involved, such as restoration of BRCA function, upregulation of nonhomologous end-joining-dependent DNA repair, induction of P-glycoprotein expression and epigenetic deregulation. Clinical implications of resistance to PARP1 inhibitors are also discussed. © 2011 Elsevier Ltd. All rights reserved.

Supuran C.T.,University of Florence
Journal of Enzyme Inhibition and Medicinal Chemistry | Year: 2016

Six genetic families of the enzyme carbonic anhydrase (CA, EC were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC-0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes. © 2015 Taylor and Francis.

Supuran C.T.,University of Florence
Expert Opinion on Drug Discovery | Year: 2017

Introduction: The enzyme carbonic anhydrase (CA, EC is found in numerous organisms across the tree of life, with seven distinct classes known to date. CA inhibition can be exploited for the treatment of edema, glaucoma, seizures, obesity, cancer and infectious diseases. A myriad of CA inhibitor (CAI) classes and inhibition mechanisms have been identified over the past decade, mainly through structure-based drug design approaches. Five different CA inhibition mechanisms are presently known. Areas covered: Recent advances in structure-based CAI design are reviewed, with periodic table-based organization of inhibitor classes. Expert opinion: Various structure-based drug design studies have led to deep understanding of factors governing tight binding and selectivity for the various isoforms. Carboxylic acids, phenols, polyamines, diols, borols, boronic acids, coumarins and sulfonamides represent successful stories which led to an anti-tumor sulfonamide in Phase I clinical trials (SLC-0111). For many inhibitor classes, no detailed crystallographic data are available. Detailed structural characterization of all CAI classes may lead to further advances in the field with potential therapeutic implications in the management of indications including neuropathic pain, cerebral ischemia, arthritis and tumor imaging. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

Pantoni L.,University of Florence
The Lancet Neurology | Year: 2010

The term cerebral small vessel disease refers to a group of pathological processes with various aetiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms. The consequences of small vessel disease on the brain parenchyma are mainly lesions located in the subcortical structures such as lacunar infarcts, white matter lesions, large haemorrhages, and microbleeds. Because lacunar infarcts and white matter lesions are easily detected by neuroimaging, whereas small vessels are not, the term small vessel disease is frequently used to describe the parenchyma lesions rather than the underlying small vessel alterations. This classification, however, restricts the definition of small vessel disease to ischaemic lesions and might be misleading. Small vessel disease has an important role in cerebrovascular disease and is a leading cause of cognitive decline and functional loss in the elderly. Small vessel disease should be a main target for preventive and treatment strategies, but all types of presentation and complications should be taken into account. © 2010 Elsevier Ltd. All rights reserved.

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