Developments in carbohydrate-based metzincin inhibitors

Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models

Orthorexia nervosa: A cross-sectional study among athletes competing in endurance sports in Northern Italy

Orthorexia Nervosa (ON) is an eating disorder marked by an excessive control over the quality of the food eaten. Some groups present a higher prevalence of ON and people practicing sports seems to be a population at risk. The aim of this study is to assess the prevalence of ON in endurance athletes and to compare their prevalence with the ones recorded in the sedentary population and in athletes playing other sports. A cross-sectional survey was carried in Piedmont and Valle d'Aosta, among 549 participants in local sports events aged between 18 and 40 years old. The questionnaire assessed socio-demographic characteristics, physical activity, nutrition and diet, the ORTO-15 questionnaire and Eating Habits Questionnaire (EHQ). The sample was stratified according to the minutes of sport practiced in a week and the type of sport played. Crosstab chi-square analyses to determine group differences on categorical variables (e.g. gender), and ANOVAs or t tests to determine group differences on continuous variables were performed. When required, post hoc analyses were performed. Linear and logistic regressions were performed in order to investigate potential predictors of orthorexia. The EHQ mean scores ware significantly higher in people who practice sports >150 minutes/week. EHQ score resulted to be positively correlated with endurance sport practice >150 minutes/week, with a coefficient of 2.407 (I.C.95% [0.27;4.54], p = 0.027). Analyses carried out suggested a correlation between endurance sport practice and ON. Further studies should be performed to identify diagnostic criteria and to compare different questionnaire used to assess them

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors

Interprofessional Communication Team for Caregivers of Patients Hospitalized in the COVID-19 Wards: Results From an Italian Experience

Background: During the COVID-19 pandemic, emergency restrictions did not allow clinician family meetings and relatives' visits. In Molinette Hospital, a new communication model between healthcare providers and families of COVID-19 affected patients was developed by a team of physicians and psychologists. The study's aims were to investigate caregivers' distress and to analyse their satisfaction with the communications provided. Methods: A cross-sectional study was conducted among caregivers of patients of Molinette Hospital COVID wards. Between April and June 2020, all caregivers were contacted 2 weeks after the patient's discharge/death to assess their satisfaction with the communications received through an online survey. Results: A total of 155 caregivers completed the survey. Caregivers' distress level was found to be higher in women than men (p = 0.048) and in caregivers whose relative died compared to the caregivers whose relative was discharged (p < 0.001). More than 85% of caregivers defined communication “excellent”/“very good”; being male was associated with higher satisfaction levels than women (β = −0.165, p = 0.046). Besides daily communication, 63 caregivers (40.6%) received additional support from a psychologist of the team. Conclusions: To our knowledge, this is the first study presenting, in an emergency, a new model of communication provided by a team of physicians and psychologists, and analyzing satisfaction with it. This model was highly appreciated by caregivers and it limited the discomfort caused by the restrictions on relatives' visits. It would be interesting to further evaluate the possibility of extending a communication model that includes doctors and psychologists in routine clinical practice

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA

Development of a fluorogenic ADAMTS-7 substrate

The extracellular protease ADAMTS-7 has been identified as a potential therapeutic target in atherosclerosis and associated diseases such as coronary artery disease (CAD). However, ADAMTS-7 inhibitors have not been reported so far. Screening of inhibitors has been hindered by the lack of a suitable peptide substrate and, consequently, a convenient activity assay. Here we describe the first fluorescence resonance energy transfer (FRET) substrate for ADAMTS-7, ATS7FP7. ATS7FP7 was used to measure inhibition constants for the endogenous ADAMTS-7 inhibitor, TIMP-4, as well as two hydroxamate-based zinc chelating inhibitors. These inhibition constants match well with IC50 values obtained with our SDS-PAGE assay that uses the N-terminal fragment of latent TGF-β–binding protein 4 (LTBP4S-A) as a substrate. Our novel fluorogenic substrate ATS7FP7 is suitable for high throughput screening of ADAMTS-7 inhibitors, thus accelerating translational studies aiming at inhibition of ADAMTS-7 as a novel treatment for cardiovascular diseases such as atherosclerosis and CAD