Mechanism of action of phthalazinone derivatives against rabies virus.

Rabies, a viral zoonosis, is responsible for almost 59,000 deaths each year, despite the existence of an effective post-exposure prophylaxis. Indeed, rabies causes acute encephalomyelitis, with a case-fatality rate of 100 % after the onset of neurological clinical signs. Therefore, the development of therapies to inhibit the rabies virus (RABV) is crucial. Here, we identified, from a 30,000 compound library screening, phthalazinone derivative compounds as potent inhibitors of RABV infection and more broadly of Lyssavirus and even Mononegavirales infections. Combining in vitro experiments, structural modelling, in silico docking and in vivo assays, we demonstrated that phthalazinone derivatives display a strong inhibition of lyssaviruses infection by acting directly on the replication complex of the virus, and with noticeable effects in delaying the onset of the clinical signs in our mouse model.

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer's disease.

BACKGROUND: Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. METHODS: Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease. RESULTS: The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. CONCLUSION: Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease.

Identification of novel FLT3 kinase inhibitors.

FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported. In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1. This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases.

New Flavonoids from Boldoa purpurascens Cav.

Phytochemical analysis of the leaves of BOLDOA PURPURASCENS Cav. led to isolation of four flavone glycosides, three of which are new compounds. Their structures have been determined by mass spectrometry and by 1 D and 2 D NMR analysis, i. e., 4',5-dihydroxy-6,7-methylenedioxyflavonol 3- O-alpha- L-rhamnopyranosyl-(1-->2)-beta- D-xylopyranoside ( 1), 4',5-dihydroxy-6,7-methylenedioxyflavonol 3- O-beta- D-xylopyranoside ( 2), and 4',5-dihydroxy-6,7-methylenedioxyflavonol 3- O-alpha- L-rhamnopyranosyl-(1-->2)-beta- D-glucopyranoside ( 3). The known compound was 4',5-dihydroxy-6,7-methylenedioxyflavonol 3- O-beta- D-glucopyranoside ( 4). The aglycone 4',5-dihydroxy-6,7-methylenedioxyflavonol is known as gomphrenol. Compounds 1 and 2 failed to show antifungal activity when tested against three different strains of fungi, i. e., FUSARIUM CULMORUM, BOTRYTIS CINEREA, and ASPERGILLUS FLAVUS.

Design, synthesis, and SAR of a novel pyrazinone series with non-nucleoside HIV-1 reverse transcriptase inhibitory activity.

A series of novel pyrazinones designed as non-nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized and their anti-HIV structure-activity relationship (SAR) was studied.

Alpha-L-fucosidases: exoglycosidases with unusual transglycosylation properties.

Apha-LFucosidases (EC 3.2.1.51), the only members of the CAZy family GH-29, are widespread glycosidases involved in many biological processes including inflammation, metastasis, and the lysosomal storage disease fucosidosis. Despite their biological significance, information concerning the mechanism of alpha-Lfucosidases has only recently become available. In an attempt to obtain further data concerning their mechanism, we have investigated the hydrolytic and transglycosylation properties of a canine and a mollusk (Pecten maximus) alpha-Lfucosidase. Our results show that, despite the evolutionary distance between these two species, both enzymes have similar hydrolysis and transglycosylation properties. Surprisingly, we found that, starting from monosaccharides, these exoglycosidases were able to catalyze efficiently the synthesis of highly branched fuco-oligosaccharides as large as tetrasaccharides, a unique feature for a wild-type exoglycosidase. The structural analysis of the compounds formed revealed that the regioselectivity of alpha-Lfucosidases is strongly influenced by the structure of the acceptor. This leads us to propose an enzymatic approach for the preparative synthesis of fuco-oligosaccharides. This will not only allow the synthesis of biological determinants containing fucose but also of new fucose-containing oligosaccharides as alpha-glycosynthases appear to be difficult to obtain.