How do physicochemical properties contribute to inhibitory activity of promising peptides against Zika Virus NS3 protease?

CONTEXT AND RESULTS: Flavivirus diseases' cycles, especially Dengue and Yellow Fever, can be observed all over Brazilian territory, representing a great health concern. Additionally, there are no drugs available in therapy. In this scenario, in silico methodologies were applied to obtain physicochemical properties, as well as to better understand the ligand-biological target interaction mode of 20 previously reported NS2B/NS3 protease inhibitors of Dengue virus. Since catalytic site of flavivirus hold similarities, such as the same catalytic triad (His51, Asp75 e Ser135), the ability of this series of molecules to fit in Zika NS3 domains can be achieved. We performed an exploratory data analysis, using statistical methodologies, such as PCA (Principal Component Analysis) and HCA (Hierarchical Component Analysis), to assist the comprehension of how physicochemical properties impact the interaction observed by the docking studies, as well as to build a correlation between the respective ranked characteristics. Based on these previous studies, peptides were selected for the dynamics simulations, which were useful to better understand the ligand-protein interactions. Information relating to, for instance, energy, ΔG, average number of hydrogen bonds and distance from Ser135 (one of the main amino acids in the catalytic pocket) were discussed. In this sense, peptides 15 (considering ΔG value and Hbond number), 7 (ΔG and energy) and 1, 6, 7 and 15 (the proximity to Ser135 throughout the dynamics simulation) were highlighted as promising. Those interesting results could contribute to future studies regarding Zika virus drug design, since this infection represents a great concern in neglected populations. METHODS: The models were constructed in the ChemDraw software. The ligand parametrization was performed in the CHEM3D 17.0, UCSF Chimera. Docking simulations were carried out in the GOLD software, after the redocking validation. We used ASP as the function score. Additionally, for dynamics simulations we applied GROMACS software, exploring, mainly, free binding energy calculations. Exploratory analysis was carried out in Minitab 17.3.1 statistical software. Prior to the exploratory analysis, data of quantum chemical properties of the peptides were collected in Microsoft Excel spreadsheet and organized to obtain Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA).

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties.

Hydroxymethylation is a simple chemical reaction, in which the introduction of the hydroxymethyl group can lead to physical-chemical property changes and offer several therapeutic advantages, contributing to the improved biological activity of drugs. There are many examples in the literature of the pharmaceutical, pharmacokinetic, and pharmacodynamic benefits, which the hydroxymethyl group can confer to drugs, prodrugs, drug metabolites, and other therapeutic compounds. It is worth noting that this group can enhance the drug's interaction with the active site, and it can be employed as an intermediary in synthesizing other therapeutic agents. In addition, the hydroxymethyl derivative can result in more active compounds than the parent drug as well as increase the water solubility of poorly soluble drugs. Taking this into consideration, this review aims to discuss different applications of hydroxymethyl derived from biological agents and its influence on the pharmacological effects of drugs, prodrugs, active metabolites, and compounds of natural origin. Finally, we report a successful compound synthesized by our research group and used for the treatment of neglected diseases, which is created from the hydroxymethylation of its parent drug.

Neglected tropical diseases and infectious illnesses: potential targeted peptides employed as hits compounds in drug design.

Neglected Tropical Diseases (NTDs) and infectious illnesses, such as malaria, tuberculosis and Zika fever, represent a major public health concern in many countries and regions worldwide, especially in developing ones. They cause thousands of deaths per year, and certainly compromise the life of affected patients. The drugs available for therapy are toxic, have considerable adverse effects, and are obsolete, especially with respect to resistance. In this context, targeted peptides are considered promising in the design of new drugs, since they have specific action and reduced toxicity. Indeed, there is a rising interest in these targeted compounds within the pharmaceutical industry, proving their importance to the Pharmaceutical Sciences field. Many have been approved by the Food and Drug Administration (FDA) to be used as medicines, plus there are more than 300 peptides currently in clinical trials. The main purpose of this review is to show the most promising potential targeted peptides acting as hits molecules in NTDs and other infectious illnesses. We hope to contribute to the discovery of medicines in this relatively neglected area, which will be extremely useful in improving the health of many suffering people.

Análisis comparativo de las pautas del consejo de organizaciones internacionales de ciencias médicas (CIOMS)2016. (Parte 3 de 3) / Comparative analysis of the standards of the council of international organizations of medical sciences (CIOMS)2016. (Part 3 of 3)

El este tercer trabajo se presenta el análisis comparativo de las últimas pautas de CIOMS 2016, realizado por estudiantes de la VI Cohorte de la Maestría en Bioética como parte de la evaluación de la asignatura Bioética e Investigación. En estas pautas se abordan de forma novedosa temas tan importantes como la investigación en grupos vulnerables, en situaciones de desastre y brotes de enfermedades de orden natural o creadas por el hombre e investigaciones con conglomerados, así como la compensación por daños, manejo de datos cuando se utiliza el entorno virtual y herramientas digitales y el conflicto de interés, lo cual proporcionará a los investigadores un aporte en su formación y una rápida adaptación a la nueva propuesta CIOMS(AU)

In this third work, the comparative analysis of the latest CIOMS 2016 guidelines, carried out by students of the VI Cohort of the Master in Bioethics, as part of the evaluation of the subject Bioethics and Research is presented. These guidelines deal in a novel way with important issues such as research in vulnerable groups in situations of disaster and outbreaks of natural or man-made diseases and investigations with clusters, as well as compensation for damages, data management when the virtual environment and digital tools and the conflict of interest are used, which will provide researchers with a contribution in their training and a rapid adaptation to the new CIOMS proposal(AU)

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs.

Malaria and tuberculosis are no longer considered to be neglected diseases by the World Health Organization. However, both are huge challenges and public health problems in the world, which affect poor people, today referred to as neglected populations. In addition, malaria and tuberculosis present the same difficulties regarding the treatment, such as toxicity and the microbial resistance. The increase of Plasmodium resistance to the available drugs along with the insurgence of multidrug- and particularly tuberculosis drug-resistant strains are enough to justify efforts towards the development of novel medicines for both diseases. This literature review provides an overview of the state of the art of antimalarial and antituberculosis chemotherapies, emphasising novel drugs introduced in the pharmaceutical market and the advances in research of new candidates for these diseases, and including some aspects of their mechanism/sites of action.

Perspectives About Self-Immolative Drug Delivery Systems.

Self-immolative drug delivery system is one of the delivery systems, which have drawn attention, in recent research, highlighting the improvement they generate in drug selectivity and efficacy. Self-immolative linkers, or spacers, are covalent groups, which have the role of cleavaging two bonds between a protector group and a drug, in the case of drug delivery systems, after a stimuli.The cascade of reactions allows to control the release of the drug. The choice of the adequate self-immolative linker is essential and depend on many variables and goals as well. Many approaches can be explored when designing a system adequate for achieving these goals, especially prodrugs. Some of the most used stimuli-responses for self-immolative drugs - enzyme triggers, chemical triggers, as pH, redox system, 1,4-, 1,6-, 1,8-eliminations, photodegradable triggers, multiple triggers, among others - are described in this ten-year review, along with their application as theranostic agents. We intend that the examples presented in this review inspire researchers working on drug delivery systems to further explore their application.

Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors.

The enzyme dihydrofolate reductase from M.tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Taking this into account, the fragment MB872 was used as a prototype for analogue development by bioisosterism/retro-bioisosterism, which resulted in 20 new substituted 3-benzoic acid derivatives. Compounds were active against MtDHFR, with IC50 values ranging from 7 to 40 µM, where compound 4e not only had the best inhibitory activity (IC50 = 7 µM), but also was 71-fold more active than the original fragment MB872. The 4e inhibition kinetics indicated an uncompetitive mechanism, which was supported by molecular modeling which suggested that the compounds can access an independent backpocket from the substrate and competitive inhibitors. Thus, based on these results, substituted 3-benzoic acid derivatives have strong potential to be developed as novel MtDHFR inhibitors and also anti-TB agents.

Searching for drugs for Chagas disease, leishmaniasis and schistosomiasis: a review.

Chagas disease, leishmaniasis and schistosomiasis are neglected diseases (NDs) and are a considerable global challenge. Despite the huge number of people infected, NDs do not create interest from pharmaceutical companies because the associated revenue is generally low. Most of the research on these diseases has been conducted in academic institutions. The chemotherapeutic armamentarium for NDs is scarce and inefficient and better drugs are needed. Researchers have found some promising potential drug candidates using medicinal chemistry and computational approaches. Most of these compounds are synthetic but some are from natural sources or are semi-synthetic. Drug repurposing or repositioning has also been greatly stimulated for NDs. This review considers some potential drug candidates and provides details of their design, discovery and activity.

Dendrimers in the context of nanomedicine.

Dendrimers are globular structures, presenting an initiator core, repetitive layers starting radially from the core and terminal groups on the surface, resembling tree architecture. These structures have been studied in many biological applications, as drug, DNA, RNA and proteins delivery, as well as imaging and radiocontrast agents. With reference to that, this review focused in providing examples of dendrimers used in nanomedicine. Although most studies emphasize cancer, there are others which reveal action in the neurosystem, reducing either neuroinflammation or protein aggregation. Dendrimers can carry bioactive compounds by covalent bond (dendrimer prodrug), or by ionic interaction or adsortion in the internal space of the nanostructure. Additionally, dendrimers can be associated with other polymers, as PEG (polyethylene glycol), and with targeting structures as aptamers, antibodies, folic acid and carbohydrates. Their products in preclinical/clinical trial and those in the market are also discussed, with a total of six derivatives in clinical trials and seven products available in the market.

A panorama of the health situation in Brazil's Federal District, 2005 to 2017. / Panorama da situação de saúde do Distrito Federal: análise do período de 2005 a 2017.

This study examines the health situation in Brazil's Federal District between 2005 and 2017. A related set of indicators were selected and compared to those for Brazil's Midwest ("Centro-Oeste") region and for the country as a whole. First, data are presented on the demographic profile and current organizational structure of the health regions and administrative areas of the Federal District. The results show that infant mortality declined from 18.3% in 2006 to 10.3% (one of the lowest in rates in Brazil) in 2016. AIDS incidence in the Federal District declined 21.3% between 2006 and 2016, a positive result when compared to data for the Midwest region and Brazil. Tuberculosis incidence and mortality rates were among the lowest in Brazil between 2006 and 2016, well below the national average, as were those for Hansen's disease, where both annual incidence and incidence of grade 2 disability decreased significantly between 2007 and 2017. Congenital syphilis in under 1 year-olds has increased in recent years in Brazil and the Midwest, and also in the Federal District, where the rate was 2.56 per 1,000 live births in 2006 and 4.7 per 1,000 live births in in 2016. These data enable managers to identify trends and challenges to be met, and inform decision-making in response to health realities in the Federal District.

Este artigo analisa a situação de saúde no Distrito Federal (DF) no período de 2005 a 2017. Um conjunto de indicadores foram selecionados e comparados aos da região Centro-Oeste (CO) e do Brasil. Inicialmente são apresentados dados sobre o perfil demográfico e a atual estrutura organizacional das regiões de saúde e áreas administrativas do DF. Os resultados mostram que o DF apresenta melhoria na taxa de mortalidade infantil, de 18,3% em 2006 para 10,3% em 2016, considerada uma das menores do país. A taxa de detecção de aids no DF apresenta tendência de queda (21,3%), entre os anos de 2006 e 2016, resultado positivo se comparado aos dados da região CO e do Brasil. Quanto à situação epidemiológica de tuberculose no DF, foi constatada, entre 2006 a 2016, um dos menores coeficientes de incidência e mortalidade do país, bem abaixo da média nacional, assim como a hanseníase com uma importante redução da taxa de detecção anual e a detecção de grau II de incapacidade, entre os anos 2007 e 2017. No caso da sífilis congênita em < de 1 ano, teve aumento nos últimos anos no Brasil, CO e no DF em 2006 apresentou uma taxa de (2,56/1.000NV) e em 2016 (4,7/1.000NV). Os dados permitem que os gestores conheçam as tendências e identifiquem os desafios para o enfrentamento e a tomada de decisão frente à realidade de saúde do DF.

The Implementation of the Monitoring and Evaluation System of the State Health Secretariat of the Brazilian Federal District (SHS/DF). / A Implantação do Sistema de Monitoramento e Avaliação da Secretaria Estadual de Saúde do Distrito Federal (SES/DF).

Through the creation of the Unified Health System (SUS), the planning processes gain intrinsic importance for the creation of public health policies and to subsidize decision-making, implementation of actions and the achievement of results. Since planning tools are fundamental to guidethe management, caution is needed regarding the interface between them,aiming at achieving the integration of health services, of which results are better, more effective and cost-effective for the government. Likewise, continuous monitoring and evaluation (M&E) processes allow the measurement and tracking of strategic information, improving the quality of health information systems and health indicators, as well as the operational and organizational performance. In this article, we present the recent initiative to implement the M&E System in the State Health Secretariat of the Federal District (SHS/DF) and the processes involved in its qualification.

Por meio da criação do Sistema Único de Saúde (SUS), os processos de planejamento ganham importância intrínseca para a formulação de políticas públicas de saúde e para subsidiar a tomada de decisões, a implementação de ações e a obtenção de resultados. Como as ferramentas de planejamento são fundamentais para orientar a gestão, é necessário o cuidado nas articulações entre elas, a fim de alcançar a integração dos serviços de saúde, cujo resultado é melhor, mais efetivo e mais barato para o governo. Da mesma forma, processos contínuos de monitoramento e avaliação (M&A) permitem medir e rastrear informações estratégicas, melhorando a qualidade dos sistemas de informação em saúde e dos indicadores de saúde, bem como do desempenho operacional e organizacional. Neste artigo, apresentamos a recente iniciativa de implementação do sistema de M&A na Secretaria de Estado da Saúde do Distrito Federal (SES/DF) e os processos envolvidos em sua qualificação.

A Implantação do Sistema de Monitoramento e Avaliação da Secretaria Estadual de Saúde do Distrito Federal (SES/DF) / The Implementation of the Monitoring and Evaluation System of the State Health Secretariat of the Brazilian Federal District (SHS/DF)

Resumo Por meio da criação do Sistema Único de Saúde (SUS), os processos de planejamento ganham importância intrínseca para a formulação de políticas públicas de saúde e para subsidiar a tomada de decisões, a implementação de ações e a obtenção de resultados. Como as ferramentas de planejamento são fundamentais para orientar a gestão, é necessário o cuidado nas articulações entre elas, a fim de alcançar a integração dos serviços de saúde, cujo resultado é melhor, mais efetivo e mais barato para o governo. Da mesma forma, processos contínuos de monitoramento e avaliação (M&A) permitem medir e rastrear informações estratégicas, melhorando a qualidade dos sistemas de informação em saúde e dos indicadores de saúde, bem como do desempenho operacional e organizacional. Neste artigo, apresentamos a recente iniciativa de implementação do sistema de M&A na Secretaria de Estado da Saúde do Distrito Federal (SES/DF) e os processos envolvidos em sua qualificação.

Abstract Through the creation of the Unified Health System (SUS), the planning processes gain intrinsic importance for the creation of public health policies and to subsidize decision-making, implementation of actions and the achievement of results. Since planning tools are fundamental to guidethe management, caution is needed regarding the interface between them,aiming at achieving the integration of health services, of which results are better, more effective and cost-effective for the government. Likewise, continuous monitoring and evaluation (M&E) processes allow the measurement and tracking of strategic information, improving the quality of health information systems and health indicators, as well as the operational and organizational performance. In this article, we present the recent initiative to implement the M&E System in the State Health Secretariat of the Federal District (SHS/DF) and the processes involved in its qualification.

Panorama da situação de saúde do Distrito Federal: análise do período de 2005 a 2017 / A panorama of the health situation in Brazil's Federal District, 2005 to 2017

Resumo Este artigo analisa a situação de saúde no Distrito Federal (DF) no período de 2005 a 2017. Um conjunto de indicadores foram selecionados e comparados aos da região Centro-Oeste (CO) e do Brasil. Inicialmente são apresentados dados sobre o perfil demográfico e a atual estrutura organizacional das regiões de saúde e áreas administrativas do DF. Os resultados mostram que o DF apresenta melhoria na taxa de mortalidade infantil, de 18,3% em 2006 para 10,3% em 2016, considerada uma das menores do país. A taxa de detecção de aids no DF apresenta tendência de queda (21,3%), entre os anos de 2006 e 2016, resultado positivo se comparado aos dados da região CO e do Brasil. Quanto à situação epidemiológica de tuberculose no DF, foi constatada, entre 2006 a 2016, um dos menores coeficientes de incidência e mortalidade do país, bem abaixo da média nacional, assim como a hanseníase com uma importante redução da taxa de detecção anual e a detecção de grau II de incapacidade, entre os anos 2007 e 2017. No caso da sífilis congênita em < de 1 ano, teve aumento nos últimos anos no Brasil, CO e no DF em 2006 apresentou uma taxa de (2,56/1.000NV) e em 2016 (4,7/1.000NV). Os dados permitem que os gestores conheçam as tendências e identifiquem os desafios para o enfrentamento e a tomada de decisão frente à realidade de saúde do DF.

Abstract This study examines the health situation in Brazil's Federal District between 2005 and 2017. A related set of indicators were selected and compared to those for Brazil's Midwest ("Centro-Oeste") region and for the country as a whole. First, data are presented on the demographic profile and current organizational structure of the health regions and administrative areas of the Federal District. The results show that infant mortality declined from 18.3% in 2006 to 10.3% (one of the lowest in rates in Brazil) in 2016. AIDS incidence in the Federal District declined 21.3% between 2006 and 2016, a positive result when compared to data for the Midwest region and Brazil. Tuberculosis incidence and mortality rates were among the lowest in Brazil between 2006 and 2016, well below the national average, as were those for Hansen's disease, where both annual incidence and incidence of grade 2 disability decreased significantly between 2007 and 2017. Congenital syphilis in under 1 year-olds has increased in recent years in Brazil and the Midwest, and also in the Federal District, where the rate was 2.56 per 1,000 live births in 2006 and 4.7 per 1,000 live births in in 2016. These data enable managers to identify trends and challenges to be met, and inform decision-making in response to health realities in the Federal District.

Targeting Groups Employed in Selective Dendrons and Dendrimers.

The design of compounds with directed action to a defined organ or tissue is a very promising approach, since it can decrease considerably the toxicity of the drug/bioactive compound. For this reason, this kind of strategy has been greatly important in the scientific community. Dendrimers, on the other hand, comprise extremely organized macromolecules with many peripheral functionalities, stepwise controlled synthesis, and defined size. These nanocomposites present several biological applications, demonstrating their efficiency to act in the pharmaceutical field. Considering that, the main purpose of this review was describing the potential of dendrons and dendrimers as drug targeting, applying different targeting groups. This application has been demonstrated through interesting examples from the literature considering the last ten years of publications.

New Advances in General Biomedical Applications of PAMAM Dendrimers.

Dendrimers are nanoscopic compounds, which are monodispersed, and they are generally considered as homogeneous. PAMAM (polyamidoamine) was introduced in 1985, by Donald A. Tomalia, as a new class of polymers, named 'starburst polymers'. This important contribution of Professor Tomalia opened a new research field involving nanotechnological approaches. From then on, many groups have been using PAMAM for diverse applications in many areas, including biomedical applications. The possibility of either linking drugs and bioactive compounds, or entrapping them into the dendrimer frame can improve many relevant biological properties, such as bioavailability, solubility, and selectivity. Directing groups to reach selective delivery in a specific organ is one of the advanced applications of PAMAM. In this review, structural and safety aspects of PAMAM and its derivatives are discussed, and some relevant applications are briefly presented. Emphasis has been given to gene delivery and targeting drugs, as advanced delivery systems using PAMAM and an incentive for its use on neglected diseases are briefly mentioned.

Lobomycosis: a therapeutic challenge.

Lobomycosis or lacaziosis is a chronic granulomatous fungal infection caused by Lacazia loboi. Most cases are restricted to tropical regions. Transmission is believed to occur through traumatic inoculation in the skin, mainly in exposed areas. It is characterized by keloid-like nodules. There are only a few hundred cases reported. The differential diagnoses include many skin conditions, and treatment is difficult. The reported case, initially diagnosed as keloid, proved to be refractory to surgical treatment alone. It was subsequently approached with extensive surgery, cryotherapy every three months and a combination of itraconazole and clofazimine for two years. No signs of clinical and histopathological activity were detected during follow-up.

Atitudes dos professores universitários dos cursos de educação física face à inclusão: um estudo exploratório de validação da versão brasileira do Peatid-III / Physical education university teacher´s attitudes toward in-clusion: an exploratory study for the validation of the brazilian version of Peatid-III / Actitudes de docentes universitarios de los cursos de educa-ción física en relacion con la inclusión: un estudio explorato-rio de validación de la versión brasileña del Peatid-III

O estudo pretende adaptar e validar uma versão para o português do Brasil do Physical Edu-cators' Attitudes toward Teaching Individuals with Disabilities-III (PEATID-III) e avaliar suas propriedades psicométricas. Participaram 76 professores de cursos de graduação em E-ducação Física de seis instituições de Educação Superior brasileira. As propriedades psicomé-tricas foram analisadas com base no r produto-momento de Pearson (teste-reteste), nos coefi-cientes de Alpha de Cronbach e na análise fatorial exploratória (com rotação Varimax). Os resultados revelaram uma estrutura global com dois fatores, que explicam 55,28% da variân-cia total. Concluiu-se que a validação da versão pode ser utilizada em docentes universitários dos cursos de Educação Física do Brasil.

The study aims to adapt and validate a Brazilian Portuguese version of Physical Educators' Attitudes towards Teaching Individuals with Disabilities-III (PEATID-III) and to evaluate its psychometric properties. Participated 76 teachers of undergraduate courses in Physical Educa-tion of six Brazilian higher education institutions. The psychometric properties were analyzed based on Pearson's product-moment (test-retest), Cronbach's Alpha coefficients and explora-tory factorial analysis (with Varimax rotation). The results revealed a global structure with two factors, which explain 55.28% of the total variance. It was concluded that the validation of the version can be used in university professors of Physical Education courses in Brazil.

El estudio tuvo como objetivo adaptar y validar una versión para el portugués de Brasil del cuestionario Physical Educators' Attitudes towards Teaching Individuals with Disabilities-III (PEATID-III) y evaluar sus propiedades psicométricas. Participaron 76 profesores de los cur-sos de graduación en Educación Física de seis instituciones de educación superior brasileña. Las propiedades psicométricas fueron analizadas con base en el momento-producto de Pear-son r (test-retest), el coeficiente alfa y el análisis factorial exploratorio (con rotación Varimax) de Cronbach. Los resultados revelaron una estructura general con dos factores que explican 55.28% de la varianza total. Se concluyó que la validación de la versión se puede utilizar en los profesores universitarios de cursos de Educación Física en Brasil.

Lobomycosis: a therapeutic challenge

Abstract: Lobomycosis or lacaziosis is a chronic granulomatous fungal infection caused by Lacazia loboi. Most cases are restricted to tropical regions. Transmission is believed to occur through traumatic inoculation in the skin, mainly in exposed areas. It is characterized by keloid-like nodules. There are only a few hundred cases reported. The differential diagnoses include many skin conditions, and treatment is difficult. The reported case, initially diagnosed as keloid, proved to be refractory to surgical treatment alone. It was subsequently approached with extensive surgery, cryotherapy every three months and a combination of itraconazole and clofazimine for two years. No signs of clinical and histopathological activity were detected during follow-up.

Dendrimer Prodrugs.

The main objective of this review is to describe the importance of dendrimer prodrugs in the design of new drugs, presenting numerous applications of these nanocomposites in the pharmaceutical field. Therefore, the use of dendrimer prodrugs as carrier for drug delivery, to improve pharmacokinetic properties of prototype, to promote drug sustained-release, to increase selectivity and, consequently, to decrease toxicity, are just some examples of topics that have been extensively reported in the literature, especially in the last decade. The examples discussed here give a panel of the growing interest dendrimer prodrugs have been evoking in the scientific community.