The search for disease-modifying agents targeted against Parkinson's disease led us to rationally design a small array of six Anle138b-centered PROTACs,
,
,
,
and
,
, targeting αSynuclein (αSyn) ...aggregates for binding, polyubiquitination by the E3 ligase Cereblon (CRBN), and proteasomal degradation. Lenalidomide and thalidomide were used as CRBN ligands and coupled with amino- and azido Anle138b derivatives through flexible linkers and coupling reactions (amidation, 'click' chemistry). Four Anle138b-PROTACs,
,
and
,
were characterized against in vitro αSyn aggregation, monitoring them in a Thioflavin T (ThT) fluorescence assay and in dopaminergic neurons derived from a set of isogenic pluripotent stem cell (iPSC) lines with SNCA multiplications. Native and seeded αSyn aggregation was determined with a new biosensor, and a partial correlation between αSyn aggregation, cellular dysfunctions, and neuronal survival was obtained. Anle138b-PROTAC
was characterized as the most promising αSyn aggregation inhibitor/degradation inducer, with potential usefulness against synucleinopathies and cancer.
SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of ...Mpro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several Mpro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 Mpro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 Mpro at a low micromolar level (IC50 = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PLpro revealed lack of inhibition, assuring the selectivity of the compound for the Mpro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells’ viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 Mpro binders.
Ancient buildings are important components of the Italian Cultural Heritage and, since the Etruscan Period, Bologna (north-eastern Italy) has always been one of the most flourishing cities both ...culturally and economically in the Italian and European panorama. The Orsi-Marconi Palace in Bologna presents a monumental façade decorated with many sandstone ornaments of the 16th century. Different samples from different parts of the façade of the building were collected and firstly characterised by macroscopic observations to determine the structural aspect. A petro-mineralogical study on the surfaces of the samples was conducted using a stereomicroscope and Optical Transmitted Light Polarized Microscopy. In addition, X-Ray Fluorescence and X-Ray Powder Diffractometer analyses were carried out to better understand the mineralogical composition of the sandstone materials used and the degradation products from the façades of this historical building. The aim of this work was to better understand how to revalue the sandstone decorations severely affected by deterioration phenomena.
Purpose: Purpose of this study is to evaluate differences in leg muscles strength and motor performance between neuromuscular taping (NT) and sham tape groups. Method: Relapsing-remitting (RR) ...multiple sclerosis (MS) patients were recruited and randomly assigned to NT or sham tape groups. All patients underwent the treatment 5 times at 5-d intervals. They were submitted to a 6-minute walk test and isokinetic test (peak torque) at the beginning (T0), at the end (T1) and 2 months after the end of the treatment (T2). Results: Forty MS patients (38 F; 2 M; mean age 45.5 ± 6.5 years) were assigned to NT group (n = 20) and to sham tape group (n = 20). Delta Peak Torque T1-T0 and T2-T0 between two groups were statistically significant in quadriceps (p = 0.007; 0.000) and hamstrings (p = 0.011; 0.007). The difference between the two groups according to 6-minute walk test was not statistically significant but in NT group it was noticed an increasing trend about the distance run. Conclusions: In this single-blind randomized controlled trial, NT seemed to increase strength in leg muscles, compared to a sham device, in RR MS patients. Further studies are needed to consider this therapy as a complement to classic physical therapy.
Implications for Rehabilitation
Neuromuscular taping (NT) in multiple sclerosis:
NT is well tolerated by multiple sclerosis patients and should be a complement to classic physical therapy.
This technique normalizes muscular function, strengthens weakened muscles and assists the postural alignment.
COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human coronavirus (hCoV) that spreads among humans and animals. Great efforts have ...been made to develop therapeutic agents to treat COVID-19, and among the available viral molecular targets, the cysteine protease SARS-CoV-2 Mpro is considered the most appealing one due to its essential role in viral replication. However, the inhibition of Mpro activity is an interesting challenge and several small molecules and peptidomimetics have been synthesized for this purpose. In this work, the Michael acceptor cinnamic ester was employed as an electrophilic warhead for the covalent inhibition of Mpro by endowing some peptidomimetic derivatives with such a functionality. Among the synthesized compounds, the indole-based inhibitors 17 and 18 efficiently impaired the in vitro replication of beta hCoV-OC-43 in the low micromolar range (EC50 = 9.14 μM and 10.1 μM, respectively). Moreover, the carbamate derivative 12 showed an antiviral activity of note (EC50 = 5.27 μM) against another hCoV, namely hCoV-229E, thus suggesting the potential applicability of such cinnamic pseudopeptides also against human alpha CoVs. Taken together, these results support the feasibility of considering the cinnamic framework for the development of new Mpro inhibitors endowed with antiviral activity against human coronaviruses.
The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 ...(1) as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind with the PD-L1 protein and challenged it in a co-culture of PD-L1 expressing cancer cells (PC9 and HCC827 cells) and peripheral blood mononuclear cells enhanced antitumor immune activity of the latter. Compound 10 significantly increased interferon γ release and apoptotic induction of cancer cells, with low cytotoxicity in healthy cells when compared to 1, thus paving the way for subsequent preclinical optimization and medical applications.
COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human coronavirus (hCoV) that spreads among humans and animals. Great efforts have ...been made to develop therapeutic agents to treat COVID-19, and among the available viral molecular targets, the cysteine protease SARS-CoV-2 M
pro
is considered the most appealing one due to its essential role in viral replication. However, the inhibition of M
pro
activity is an interesting challenge and several small molecules and peptidomimetics have been synthesized for this purpose. In this work, the Michael acceptor cinnamic ester was employed as an electrophilic warhead for the covalent inhibition of M
pro
by endowing some peptidomimetic derivatives with such a functionality. Among the synthesized compounds, the indole-based inhibitors
17
and
18
efficiently impaired the
in vitro
replication of beta hCoV-OC-43 in the low micromolar range (EC
50
= 9.14 μM and 10.1 μM, respectively). Moreover, the carbamate derivative
12
showed an antiviral activity of note (EC
50
= 5.27 μM) against another hCoV, namely hCoV-
229E
, thus suggesting the potential applicability of such cinnamic pseudopeptides also against human alpha CoVs. Taken together, these results support the feasibility of considering the cinnamic framework for the development of new M
pro
inhibitors endowed with antiviral activity against human coronaviruses.
A panel of novel cinnamic ester derivatives showed a potent inhibitory effect against SARS-CoV-2 M
pro
and efficiently impaired the
in vitro
replication of two human coronaviruses in the low micromolar range.
COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human coronavirus (hCoV) that spreads among humans and animals. Great efforts have ...been made to develop therapeutic agents to treat COVID-19, and among the available viral molecular targets, the cysteine protease SARS-CoV-2 M
is considered the most appealing one due to its essential role in viral replication. However, the inhibition of M
activity is an interesting challenge and several small molecules and peptidomimetics have been synthesized for this purpose. In this work, the Michael acceptor cinnamic ester was employed as an electrophilic warhead for the covalent inhibition of M
by endowing some peptidomimetic derivatives with such a functionality. Among the synthesized compounds, the indole-based inhibitors 17 and 18 efficiently impaired the
replication of beta hCoV-OC-43 in the low micromolar range (EC
= 9.14 μM and 10.1 μM, respectively). Moreover, the carbamate derivative 12 showed an antiviral activity of note (EC
= 5.27 μM) against another hCoV, namely hCoV-229E, thus suggesting the potential applicability of such cinnamic pseudopeptides also against human alpha CoVs. Taken together, these results support the feasibility of considering the cinnamic framework for the development of new M
inhibitors endowed with antiviral activity against human coronaviruses.
Glioblastoma Multiforme (GBM) is a highly invasive primary brain tumour characterized by chemo- and radio-resistance and poor overall survival. GBM can present an aberrant functionality of p53, ...caused by the overexpression of the murine double minute 2 protein (MDM2) and its analogue MDM4, which may influence the response to conventional therapies. Moreover, tumour resistance/invasiveness has been recently attributed to an overexpression of the chemokine receptor CXCR4, identified as a pivotal mediator of glioma neovascularization. Notably, CXCR4 and MDM2-4 cooperate in promoting tumour invasion and progression. Although CXCR4 actively promotes MDM2 activation leading to p53 inactivation, MDM2-4 knockdown induces the downregulation of CXCR4 gene transcription.
Our study aimed to assess if the CXCR4 signal blockade could enhance glioma cells’ sensitivity to the inhibition of the p53-MDMs axis. Rationally designed inhibitors of MDM2/4 were combined with the CXCR4 antagonist, AMD3100, in human GBM cells and GBM stem-like cells (neurospheres), which are crucial for tumour recurrence and chemotherapy resistance. The dual MDM2/4 inhibitor RS3594 and the CXCR4 antagonist AMD3100 reduced GBM cell invasiveness and migration in single-agent treatment and mainly in combination. AMD3100 sensitized GBM cells to the antiproliferative activity of RS3594. It is noteworthy that these two compounds present synergic effects on cancer stem components: RS3594 inhibited the growth and formation of neurospheres, AMD3100 induced differentiation of neurospheres while enhancing RS3594 effectiveness preventing their proliferation/clonogenicity. These results confirm that blocking CXCR4/MDM2/4 represents a valuable strategy to reduce GBM proliferation and invasiveness, acting on the stem cell component too.
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