In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine.

Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina®, and the molecular dynamic with Gromacs®. Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and ß2 adrenoreceptor.

Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines.

BACKGROUND: In recent years, an increase in the occurrence of illnesses caused by two clinically- important arboviruses has been reported: Zika virus (ZIKV) and Chikungunya virus (CHIKV). There is no licensed antiviral treatment for either of the two abovementioned viruses. Bearing in mind that the antiviral effect of indole alkaloids has been reported for other arboviral models, the present study proposed to evaluate the antiviral in vitro and in silico effects of four indole alkaloids on infections by these two viruses in different cell lines. METHODS: The antiviral effects of voacangine (VOAC), voacangine-7-hydroxyindolenine (VOAC-OH), rupicoline and 3-oxo voacangine (OXO-VOAC) were evaluated in Vero, U937 and A549 cells using different experimental strategies (Pre, Trans, Post and combined treatment). Viral infection was quantified by different methodologies, including infectious viral particles by plating, viral genome by RT-qPCR, and viral protein by cell ELISA. Moreover, molecular docking was used to evaluate the possible interactions between structural and nonstructural viral proteins and the compounds. The results obtained from the antiviral strategies for each experimental condition were compared in all cases with the untreated controls. Statistically significant differences were identified using a parametric Student's t-test. In all cases, p values below 0.05 (p < 0.05) were considered statistically significant. RESULTS: In the pre-treatment strategy in Vero cells, VOAC and VOAC-OH inhibited both viral models and OXO-VOAC inhibited only ZIKV; in U937 cells infected with CHIKV/Col, only VOAC-OH inhibited infection, but none of the compounds had activity in A549 cells; in U937 cells and A549 cells infected with ZIKV/Col, the three compounds that were effective in Vero cells also had antiviral activity. In the trans-treatment strategy, only VOAC-OH was virucidal against ZIKV/Col. In the post-treatment strategy, only rupicoline was effective in the CHIKV/Col model in Vero and A549 cells, whereas VOAC and VOAC-OH inhibited ZIKV infection in all three cell lines. In the combined strategy, VOAC, VOAC-OH and rupicoline inhibited CHIKV/Col and ZIKV/Col, but only rupicoline improved the antiviral effect of ZIKV/Col-infected cultures with respect to the individual strategies. Molecular docking showed that all the compounds had favorable binding energies with the structural proteins E2 and NSP2 (CHIKV) and E and NS5 (ZIKV). CONCLUSIONS: The present study demonstrates that indole alkaloids are promising antiviral drugs in the process of ZIKV and CHIKV infection; however, the mechanisms of action evaluated in this study would indicate that the effect is different in each viral model and, in turn, dependent on the cell line.

The Antiviral and Virucidal Activities of Voacangine and Structural Analogs Extracted from Tabernaemontana cymosa Depend on the Dengue Virus Strain.

Currently, no specific licensed antiviral exists for treating the illness caused by dengue virus (DENV). Therefore, the search for compounds of natural origin with antiviral activity is an important area of research. In the present study, three compounds were isolated and identified from seeds of Tabernaemontana cymosa plants. The in vitro antiviral effect of those compounds and voacangine against different DENV strains was assessed using different experimental approaches: compounds added before the infection (Pre), at the same time with the virus (Trans), after the infection (Post) or compounds present in all moments of the experiment (Pre-Trans-Post, Combined treatment). In silico studies (docking and molecular dynamics) were also performed to explain the possible antiviral mechanisms. The identified compounds were three structural analogs of voacangine (voacangine-7-hydroxyindolenine, rupicoline and 3-oxo-voacangine). In the Pre-treatment, only voacangine-7-hydroxyindolenine and rupicoline inhibited the infection caused by the DENV-2/NG strain (16.4% and 29.6% infection, respectively). In the Trans-treatment approach, voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited the infection in both DENV-2/NG (11.2%, 80.4% and 75.7% infection, respectively) and DENV-2/16681 infection models (73.7%, 74.0% and 75.3% infection, respectively). The latter strain was also inhibited by 3-oxo-voacangine (82.8% infection). Moreover, voacangine (most effective virucidal agent) was also effective against one strain of DENV-1 (DENV-1/WestPac/74) and against the third strain of DENV-2 (DENV-2/S16803) (48.5% and 32.4% infection, respectively). Conversely, no inhibition was observed in the post-treatment approach. The last approach (combined) showed that voacangine, voacangine-7-hydroxyindolenine and rupicoline inhibited over 90% of infections (3.5%, 6.9% and 3.5% infection, respectively) of both strains (DENV-2/NG and DENV-2/16681). The free energy of binding obtained with an in silico approach was favorable for the E protein and compounds, which ranged between -5.1 and -6.3 kcal/mol. Finally, the complex formed between DENV-2 E protein and the best virucidal compound was stable for 50 ns. Our results show that the antiviral effect of indole alkaloids derived from T. cymose depends on the serotype and the virus strain.

Antiviral Role of Phenolic Compounds against Dengue Virus: A Review.

Phenolic compounds have been related to multiple biological activities, and the antiviral effect of these compounds has been demonstrated in several viral models of public health concern. In this review, we show the antiviral role of phenolic compounds against dengue virus (DENV), the most widespread arbovirus globally that, after its re-emergence, has caused multiple epidemic outbreaks, especially in the last two years. Twenty phenolic compounds with anti-DENV activity are discussed, including the multiple mechanisms of action, such as those directed against viral particles or viral proteins, host proteins or pathways related to the productive replication viral cycle and the spread of the infection.

Representaciones sociales sobre salud en adolescentes habitantes de calle, Medellín 2014 / Social representations of health in adolescents living on the street, Medellin 2014

RESUMEN Introducción: En Medellín se desconocen las representaciones sociales sobre salud en habitantes de calle. Objetivo: Comprender las representaciones sociales sobre el proceso salud-enfermedad y enfermedades transmisibles en niños y adolescentes habitantes de calle, Medellín. Materiales y método: Teoría fundamentada con 20 personas pertenecientes a un programa educativo para personas de la calle, seleccionadas por muestreo teórico. Se realizaron entrevistas, diarios de campo, observación participante y no participante; codificación abierta, axial y selectiva; triangulación metodológica, investigativa y teórica. Se aplicaron los criterios de credibilidad, auditabilidad y transferibilidad. Resultados: La salud es un proceso determinado por los dominios histórico, social y empírico; ésta presenta tres dimensiones, la ambiental, la física y la emocional, siendo la última un elemento marginal en el grupo estudiado. La salud es multidimensional mientras que la enfermedad está circunscrita a lo físico; en consecuencia, los recursos terapéuticos se limitan a la intervención de alteraciones orgánicas. Las estrategias de intervención de la enfermedad giran en torno de la auto-atención y la atención por pares; mientras que los servicios de salud institucionalizados representan lo negativo en tanto constituyen espacios de estigmatización y eliminación de barreras protectoras como "el mugre". El grupo presenta una teoría de la causalidad de las infecciones ligada a la contaminación ambiental y la violencia. Conclusión: Las representaciones sociales de la salud en el grupo de estudio distan de visiones hegemónicas que vindican su holismo, los dominios físico y ambiental constituyen el centro de sus referentes teóricos y prácticos frente a la enfermedad. MÉD.UIS. 2016;29(3):33-42.

ABSTRACT Introduction: In Medellín the social representations of health in people of the street are unknown. Objective: To understand the social representations of health and communicable diseases in homeless young, Medellín. Materials and method: Grounded theory with 20 persons belonging to an educational program for homeless young, selected by theoretical sampling. Interviews, field notes, participant and non participant were conducted; open, axial and selective coding were done; and methodological, research and theoretical triangulation. The criteria of credibility, auditability and transferability were applied. Results: Health is determined by the historical, social and empirical domains; it has three dimensions, environmental, physical and emotional, the last being a fringe element in the group studied. Health is multidimensional while the disease is confined to the physical; therefore, resources therapeutic are limited to the intervention of organic alterations. Intervention strategies for the disease revolve around self-care and peer attention; while institutionalized health services, particularly hospitals, representing negative spaces because in this places are stigmatized and the health professionals removal the protective barriers as "filth". The group presents a theory of causation of communicable diseases linked to the environmental pollution and violence. Conclusion: The social representations of health in the study group are far from hegemonic visions that vindicate his holism, physical and environmental domains are at the center of its theoretical framework and practical against disease. MÉD.UIS. 2016;29(3):33-42.