AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs.

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT's alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT's alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.

A Systematic Review and Narrative Synthesis of Factors Affecting Pre-exposure Prophylaxis Willingness Among Black Women for HIV Prevention.

Pre-exposure prophylaxis (PrEP) can significantly reduce human immunodeficiency virus (HIV) transmission among Black women in the United States (U.S.), a group disproportionately affected by HIV. However, PrEP uptake in this HIV-vulnerable population is low. This review analyzes the factors influencing Black women's PrEP willingness using the Behavioral Model for Vulnerable Populations (BMVP). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Population, Intervention, Comparison, Outcome, Study Design (PICOS) framework, we conducted a systematic literature search and selected 24 peer-reviewed studies on PrEP willingness. Narrative synthesis revealed a heterogeneous landscape of the determinants affecting PrEP willingness among Black women, categorized into three main domains. Predisposing demographic and social factors included younger age, unmarried status, higher education, sexual or gender minority identity, trust in healthcare providers, and perceived HIV risk. Predisposing behavioral factors included condomless sex, multiple partners, and engagement in sex work. Socioeconomic status, health insurance, healthcare access, support systems, and structural challenges were identified as enabling factors influencing Black women's PrEP willingness. Finally, the perceived need domain and health-related factors influencing the perceived need for PrEP included a history of sexually transmitted infections (STI), intimate partner violence (IPV), and birth control interference. This study emphasizes the complexity of the barriers and facilitators of PrEP uptake and, thus, the need for tailored interventions and health strategies to promote its use. Addressing the interconnected individual, interpersonal, and structural determinants of PrEP access is crucial for improving PrEP willingness and thereby advancing health equity in this population.

RESUMEN: La profilaxis preexposición (PrEP) puede reducir significativamente la transmisión del virus de la inmunodeficiencia humana (VIH) entre las mujeres negras en los Estados Unidos (EE.UU.), un grupo desproporcionadamente afectado por el VIH. Sin embargo, la adopción de PrEP en esta población vulnerable al VIH es baja. Esta revisión analiza los factores que influyen en la disposición de las mujeres negras para usar PrEP utilizando el Modelo Conductual para Poblaciones Vulnerables (BMVP). Siguiendo las directrices de los elementos de informes preferidos para revisiones sistemáticas y metanálisis (PRISMA) y el marco de población, intervención, comparación, resultado, diseño del estudio (PICOS), realizamos una búsqueda bibliográfica sistemática en cinco bases de datos electrónicas y seleccionamos 24 estudios revisados por pares sobre la disposición a usar PrEP que cumplen con los criterios de inclusión predefinidos. La síntesis narrativa reveló un panorama heterogéneo de los determinantes que afectan la disposición a usar PrEP entre las mujeres negras, categorizados en tres dominios principales. Los factores demográficos y sociales predisponentes incluían la edad más joven, el estado civil soltero, la educación superior, la identidad sexual o de género minoritaria, la confianza en los proveedores de atención médica y el riesgo percibido de VIH. Los factores de comportamiento predisponentes, que abarcan comportamientos que se relacionan directamente con el riesgo de VIH, incluían el sexo sin condón, tener múltiples parejas y participar en el trabajo sexual. En cuanto al dominio habilitador, se identificaron el estatus socioeconómico, el seguro de salud, el acceso a la atención médica, los sistemas de apoyo y los desafíos estructurales como factores que influyen en la disposición de las mujeres negras para tomar PrEP. Finalmente, los factores de necesidad percibida y relacionados con la salud identificados incluían tener un historial de infecciones de transmisión sexual (ITS), violencia de pareja íntima (VPI) y la interferencia del control de la natalidad, todos los cuales influyen en la necesidad percibida de PrEP. Este estudio enfatiza la complejidad de las barreras y facilitadores de la adopción de PrEP, destacando la importancia de intervenciones y estrategias de salud personalizadas para promover su uso. Abordar los determinantes interconectados a nivel individual, interpersonal y estructural del acceso a PrEP es crucial para mejorar la disposición a usar PrEP, avanzando así la equidad en salud dentro de este grupo vulnerable con fuertes razones para la prevención del VIH.

Evaluation of Rhodanine Indolinones as AANAT Inhibitors.

Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N-acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X-ray crystal-based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine-indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5-carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency.