{"id":286611,"date":"2024-10-29T10:00:25","date_gmt":"2024-10-29T09:00:25","guid":{"rendered":"https:\/\/www.cbm.uam.es\/?p=286611"},"modified":"2024-11-04T11:56:13","modified_gmt":"2024-11-04T10:56:13","slug":"el-antiviral-remdesivir-un-analogo-de-nucleotido-es-un-sustrato-valido-para-iniciar-la-sintesis-de-adn-por-la-proteina-primpol","status":"publish","type":"post","link":"https:\/\/www.cbm.uam.es\/index.php\/2024\/10\/29\/el-antiviral-remdesivir-un-analogo-de-nucleotido-es-un-sustrato-valido-para-iniciar-la-sintesis-de-adn-por-la-proteina-primpol\/","title":{"rendered":"El antiviral remdesivir, un an\u00e1logo de nucle\u00f3tido, es un sustrato v\u00e1lido para iniciar la s\u00edntesis de ADN por la prote\u00edna PrimPol"},"content":{"rendered":"<p>El remdesivir es un f\u00e1rmaco antiviral de amplio espectro que ha sido aprobado para el tratamiento de la COVID-19 en pacientes de alto riesgo, y que es eficiente contra diferentes virus de ARN, tales como otros coronavirus (MERS), flavovirus (\u00c9bola) y paramixovirus (virus sincitial humano, que provoca bronquiolitis en lactantes).<\/p>\n<p>El material gen\u00e9tico de estos virus es diferente al de nuestras c\u00e9lulas, ya que est\u00e1 contenido en mol\u00e9culas de ARN en vez de ADN. Durante la multiplicaci\u00f3n de estos virus, su material gen\u00e9tico debe multiplicarse tambi\u00e9n, y las prote\u00ednas encargadas de este proceso son ARN polimerasas virales dependientes de ARN. Para ello, utilizan nucle\u00f3tidos como si fueran bloques de construcci\u00f3n. El remdesivir se metaboliza <em>in vivo<\/em> a la forma activa remdesivir trifosfato (RTP), una mol\u00e9cula muy similar o an\u00e1loga del nucle\u00f3tido adenosina trifosfato (ATP), uno de los bloques que construyen nuestro ARN. Durante el proceso de multiplicaci\u00f3n del material gen\u00e9tico de los virus de ARN, sus polimerasas pueden utilizar RTP como sustrato para la s\u00edntesis del ARN.<\/p>\n<p>Una vez incorporado en el material gen\u00e9tico del virus, el remdesivir act\u00faa como terminador de cadena, bloqueando la s\u00edntesis del ARN viral. Debido a esto, puede ser utilizado como antiviral, adem\u00e1s sin toxicidad celular ya que no se incorpora en nuestro ADN. Sin embargo, se ha descrito recientemente que la polimerasa replicativa mitocondrial (Pol\u03b3) tambi\u00e9n se bloquea <em>in vitro<\/em> por RTP. A pesar de esto, el impacto del RTP <em>in vivo<\/em> en la s\u00edntesis del ADN mitocondrial es escaso.<\/p>\n<p>En este estudio, investigadores del Centro de Biolog\u00eda Molecular Severo Ochoa (CBM, CSIC-UAM) han estudiado el posible papel protector de la PrimPol humana en la s\u00edntesis del ADN mitocondrial. Esta prote\u00edna tambi\u00e9n opera en la mitocondria, facilitando la replicaci\u00f3n del ADN mitocondrial mediante la producci\u00f3n de unas mol\u00e9culas peque\u00f1as llamadas iniciadores, y siendo as\u00ed capaz de rescatar el bloqueo causado por el RTP.<\/p>\n<p>Los resultados del trabajo mostraron que el RTP es un sustrato v\u00e1lido para la producci\u00f3n de los iniciadores por parte de PrimPol<em>, <\/em>pero no para su posterior incorporaci\u00f3n en el ADN durante el proceso de elongaci\u00f3n. Adem\u00e1s, los iniciadores con RTP son abortivos, ya que no permiten la elongaci\u00f3n del ADN, especialmente cuando hay lesiones en la mol\u00e9cula de ADN que se usa como molde para la s\u00edntesis.<\/p>\n<p>Adem\u00e1s, la incorporaci\u00f3n de RTP al iniciador requiere una concentraci\u00f3n cinco veces mayor que la del sustrato natural de PrimPol, el ATP. Teniendo en cuenta que la concentraci\u00f3n de ATP en la c\u00e9lula es mucho mayor que la de RTP, es poco probable que PrimPol utilice RTP <em>in vivo<\/em> para producir los iniciadores, durante un tratamiento con remdesivir.<\/p>\n<p>Por lo tanto, PrimPol podr\u00eda continuar realizando su funci\u00f3n protectora de la replicaci\u00f3n mitocondrial en pacientes que est\u00e9n recibiendo tratamiento antiviral con remdesivir, aliviando la toxicidad del mismo.<\/p>\n<p>&nbsp;<\/p>\n<h3>Referencia:<\/h3>\n<p>Jim\u00e9nez-Juliana M, Mart\u00ednez-Jim\u00e9nez MI, Blanco L. Remdesivir triphosphate is a valid substrate to initiate synthesis of DNA primers by human PrimPol. DNA Repair (Amst). 2024 Nov;143:103772. DOI: <a href=\"https:\/\/doi.org\/10.1016\/j.dnarep.2024.103772\">10.1016\/j.dnarep.2024.103772<\/a><\/p>\n<p>&nbsp;<\/p>\n<h3>Contacto:<\/h3>\n<p><a href=\"mailto:Comunicacion@cbm.csic.es\">Comunicacion@cbm.csic.es<\/a><\/p>\n<p>Mar\u00eda Isabel Mart\u00ednez Jim\u00e9nez, maria_m@cbm.csic.es<\/p>\n<p>Luis Blanco Davila, lblanco@cbm.csic.es<\/p>\n","protected":false},"excerpt":{"rendered":"<p>El remdesivir es un f\u00e1rmaco antiviral de amplio espectro que ha sido aprobado para el tratamiento de la COVID-19 en pacientes de alto riesgo, y que es eficiente contra diferentes [&hellip;]<\/p>\n","protected":false},"author":5,"featured_media":286614,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"","_et_pb_old_content":"","_et_gb_content_width":"","footnotes":""},"categories":[44,54],"tags":[],"class_list":["post-286611","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news","category-scientific-article"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - 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