APPAGATO: an APproximate PArallel and stochastic GrAph querying TOol for biological networks

Motivation: Biological network querying is a problem requiring a considerable computational effort tobe solved. Given a target and a query network, it aims to find occurrences of the query in the target byconsidering topological and node similarities (i.e. mismatches between nodes, edges, or node labels).Querying tools that deal with similarities are crucial in biological network analysis since they providemeaningful results also in case of noisy data. In addition, since the size of available networks increasessteadily, existing algorithms and tools are becoming unsuitable. This is rising new challenges for the designof more efficient and accurate solutions.Results: This paper presents APPAGATO, a stochastic and parallel algorithm to find approximateoccurrences of a query network in biological networks. APPAGATO handles node, edge, and node labelmismatches. Thanks to its randomic and parallel nature, it applies to large networks and, compared toexisting tools, it provides higher performance as well as statistically significant more accurate results.Tests have been performed on protein-protein interaction networks annotated with synthetic and real geneontology terms. Case studies have been done by querying protein complexes among different species andtissue

Synthesis of SARS-CoV-2 Mpro inhibitors bearing a cinnamic ester warhead with in vitro activity against human coronaviruses

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

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

Progettazione, sintesi e attivita' anticonvulsante di nuovi antagonisti del recettore AMPA

Dottorato di ricerca in scienze farmaceutiche. 12. ciclo. A.a. 1996-99. Tutore Silvana Grasso. Coordinatore Pietro Monforte.Consiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

Hydrogels for the Delivery of Plant-Derived (Poly)Phenols

This review deals with hydrogels as soft and biocompatible vehicles for the delivery of plant-derived (poly)phenols, compounds with low general toxicity and an extraordinary and partially unexplored wide range of biological properties, whose use presents some major issues due to their poor bioavailability and water solubility. Hydrogels are composed of polymeric networks which are able to absorb large amounts of water or biological fluids while retaining their three-dimensional structure. Apart from this primary swelling capacity, hydrogels may be easily tailored in their properties according to the chemical structure of the polymeric component in order to obtain smart delivery systems that can be responsive to various internal/external stimuli. The functionalization of the polymeric component of hydrogels may also be widely exploited to facilitate the incorporation of bioactive compounds with different physicochemical properties into the system. Several prototype hydrogel systems have been designed for effective polyphenol delivery and potential employment in the treatment of human diseases. Therefore, the inherent features of hydrogels have been the focus of considerable research efforts over the past few decades. Herein, we review the most recent advances in (poly)phenol-loaded hydrogels by analyzing them primarily from the therapeutic perspective and highlighting the innovative aspects in terms of design and chemistry

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections

Cyrene: A Green Solvent for the Synthesis of Bioactive Molecules and Functional Biomaterials

In the panorama of sustainable chemistry, the use of green solvents is increasingly emerging for the optimization of more eco-friendly processes which look to a future of biocompatibility and recycling. The green solvent Cyrene, obtained from biomass via a two-step synthesis, is increasingly being introduced as the solvent of choice for the development of green synthetic transformations and for the production of biomaterials, thanks to its interesting biocompatibility, non-toxic and non-mutagenic properties. Our review offers an overview of the most important organic reactions that have been investigated to date in Cyrene as a medium, in particular focusing on those that could potentially lead to the formation of relevant chemical bonds in bioactive molecules. On the other hand, a description of the employment of Cyrene in the production of biomaterials has also been taken into consideration, providing a point-by-point overview of the use of Cyrene to date in the aforementioned fields