Natural Products-Based Drug Design against SARS-CoV-2 Mpro 3CLpro

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil’s semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARSCoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.Research Dean and Graduate Studies of the Federal University of Pará (PROPESP/UFPA)Brazilian National Council for Scientific and Technological Development (CNPq)Brazilian Coordination for Improvement of Personnel Higher Education (CAPES)Bahia Research Foundation (FAPESB, grant numbers APP071/2011, JCB-0039/2013, and RED-008/2013

School Evasion in the Brazilian trends: analyzing the vectors that influence students’ decision to interrupt their formative process

Research data demonstrate that the analyzes built around School Evasion considers, primarily, the quantitative metrics of studentsrsquo; entry and exit and also the monetary losses, especially because it would be incoherent not to take as reference the goals and objectives outlined for education school system. However, analyzing the vectors that influence studentsrsquo; decision to interrupt their formative process, according to purely numerical criteria, would imply in ignoring the function of educational institutions and the real causes/reasons stemming from the social and relational demand of students' passage on educational institutions. For this reason, problematizing some of the recurring issues and incidents generated by certain investigations seems instigating and challenging. If in on the one hand, the attitude of understanding the conceptualization, the investigative tendencies and the characteristics of the studies give rise to certain criticisms that put in check the complexity of the object in question, on the other, it can stimulate the construction of other tendencies, new pathways, other possible ways of overcoming the gaps identified in the studies about School Evasion in Brazil

Detecting new physics contributions to the D0-D0bar mixing through their effects on B decays

New physics effects may yield a detectable mass difference in the D0-D0bar system, Delta m_D. Here we show that this has an important impact on some B --> D decays. The effect involves a new source of CP violation, which arises from the interference between the phases in the B --> D decays and those in the D0-D0bar system. This interference is naturally large. New physics may well manifest itself through Delta m_D contributions to these B decays.Comment: 10 pages, Revtex, no figures. To appear in PR

Exciton bimolecular annihilation dynamics in supramolecular nanostructures of conjugated oligomers

We present femtosecond transient absorption measurements on $\pi$-conjugated supramolecular assemblies in a high pump fluence regime. Oligo(\emph{p}-phenylenevinylene) monofunctionalized with ureido-\emph{s}-triazine (MOPV) self-assembles into chiral stacks in dodecane solution below 75$^{\circ}$C at a concentration of $4\times 10^{-4}$ M. We observe exciton bimolecular annihilation in MOPV stacks at high excitation fluence, indicated by the fluence-dependent decay of $1^1$B$_{u}$-exciton spectral signatures, and by the sub-linear fluence dependence of time- and wavelength-integrated photoluminescence (PL) intensity. These two characteristics are much less pronounced in MOPV solution where the phase equilibrium is shifted significantly away from supramolecular assembly, slightly below the transition temperature. A mesoscopic rate-equation model is applied to extract the bimolecular annihilation rate constant from the excitation fluence dependence of transient absorption and PL signals. The results demonstrate that the bimolecular annihilation rate is very high with a square-root dependence in time. The exciton annihilation results from a combination of fast exciton diffusion and resonance energy transfer. The supramolecular nanostructures studied here have electronic properties that are intermediate between molecular aggregates and polymeric semiconductors

Dye-sensitized solar cells based on dimethylamino-π-bridge-pyranoanthocyanin dyes

UID/QUI/50006/2019 PTDC/QEQ-QFI/1971/2014 PD/BD/135087/2017 SFRH/BD/136556/2018 SFRH/BD/143309/2019 IF/00225/2015 DL57/2016 Program Contract (HC). UID/CTM/50025/2019 PTDC/CTM-ENE/5125/2014 CNPq 444061/2018-5 Universal grant 408181/2016-3The pyranoanthocyanins present in red wine display great potential as photosensitizers in bio-inspired Dye-Sensitized Solar Cells (DSSCs). Following a biomimetic approach, a series of amino-π-bridge-pyranoanthocyanin derivatives were employed as dye sensitizers in DSSCs. The dimethylamine group was selected to take advantage of its electron-donor character and the possibility of ‘dual-mode anchoring’ ([sbnd]OH vs. dimethylamino) to titanium dioxide. The increase in π-conjugation via insertion of C[dbnd]C bonds affected molecule flexibility, electron-donor ability and the pH-dependent equilibria of the pyranoanthocyanin derivatives. The current vs. potential properties of photoanodes using these dyes pointed to essential features of the relationship between power conversion efficiency and dye structure. These included the influences of the dimethylamine group, of π-conjugation and of substitution in ring B on the adsorption of the dyes to TiO2 and on the overall performance of the DSSCs prepared from them with and without added acid. An overall efficiency of 2.55% was obtained for the best performing compound, 4-(dimethylamino)-cinnamyl-pyranocyanidin-3-O-glucoside (JO3), which consolidates the importance of this family of compounds as potential dye-sensitizers for DSSC applications.authorsversionpublishe

Antimicrobial resistance profiling of Salmonella enterica distinct serotypes isolated from pork in São Paulo

Salmonellosis still is one of the most important worldwide zoonosis due to its high endemicity, mortality, and difficulty in control (Stevens et al., 2009). In the São Paulo city, different realities regarding good production practices and quality control of animal products coexists, especially when considering points of direct consumer sales. The aim of this study was to evaluate the antimicrobial resistance profiles of Salmonella enterica distinct serotypes isolated from pork in São Paulo

Evidence of a noncoding transcript of the RIPK2 gene overexpressed in head and neck tumor

Receptor-interacting proteins are a family of serine/threonine kinases, which integrate extra and intracellular stress signals caused by different factors, including infections, inflammation and DNA damage. Receptor-interacting serine/threonine-protein kinase 2 (RIP-2) is a member of this family and an important component of the nuclear factor NF-kappa-B signaling pathway. The corresponding human gene RIPK2 generates two transcripts by alternative splicing, the full-length and a short transcript. The short transcript has a truncated 5? sequence, which results in a predicted isoform with a partial kinase domain but able to transduce signals through its caspase recruitment domain. In this study, the expression of RIPK2 was investigated in human tissue samples and, in order to determine if both transcripts are similarly regulated at the transcriptional level, cancer cell lines were submitted to temperature and acid stresses. We observed that both transcripts are expressed in all tissues analyzed, with higher expression of the short one in tumor samples, and they are differentially regulated following temperature stress. Despite transcription, no corresponding protein for the short transcript was detected in tissues and cell lines analyzed. We propose that the shorter transcript is a noncoding RNA and that its presence in the cell may play regulatory roles and affect inflammation and other biological processes related to the kinase activity of RIP-2.Fil: Mancini Villagra, Ulises Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: da Cunha, Bianca R.. Universidade de Sao Paulo; BrasilFil: Polachini, Giovana M.. No especifíca;Fil: Tiago, Tiago Henrique. No especifíca;Fil: Carlos H. T. P. da Silva. Universidade de Sao Paulo; BrasilFil: Feitosa, Olavo A.. Universidade de Sao Paulo; BrasilFil: Fukuyama, Erica E.. Arnaldo Vieira de Carvalho Cancer Institute; BrasilFil: López, Rossana V. M.. No especifíca;Fil: Dias Neto, Emmanuel. Universidade de Sao Paulo; BrasilFil: Nunes, Fabio D.. Universidade de Sao Paulo; BrasilFil: Severino, Patricia. Hospital Israelita Albert Einstein; BrasilFil: Tajara, Eloiza Helena Tajara. Universidade de Sao Paulo; Brasi

Benznidazole biotransformation and multiple targets in <i>Trypanosoma</i> cruzi revealed by metabolomics

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The first line treatment for Chagas disease, a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, involves administration of benznidazole (Bzn). Bzn is a 2-nitroimidazole pro-drug which requires nitroreduction to become active, although its mode of action is not fully understood. In the present work we used a non-targeted MS-based metabolomics approach to study the metabolic response of T. cruzi to Bzn.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methodology/Principal findings&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Parasites treated with Bzn were minimally altered compared to untreated trypanosomes, although the redox active thiols trypanothione, homotrypanothione and cysteine were significantly diminished in abundance post-treatment. In addition, multiple Bzn-derived metabolites were detected after treatment. These metabolites included reduction products, fragments and covalent adducts of reduced Bzn linked to each of the major low molecular weight thiols: trypanothione, glutathione, γ-glutamylcysteine, glutathionylspermidine, cysteine and ovothiol A. Bzn products known to be generated in vitro by the unusual trypanosomal nitroreductase, TcNTRI, were found within the parasites, but low molecular weight adducts of glyoxal, a proposed toxic end-product of NTRI Bzn metabolism, were not detected.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions/significance&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Our data is indicative of a major role of the thiol binding capacity of Bzn reduction products in the mechanism of Bzn toxicity against T. cruzi