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...
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.
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