RESUMEN
Nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) constitutes an essential inflammasome sensor protein, pivotal in the orchestration of innate immunity. Given its paramount role, NLRP3 has recently emerged as an enticing therapeutic target for disorders associated with inflammation. In this study, we embarked on the design and synthesis of two series of compounds, endowed with the capacity to induce NLRP3 degradation via autophagy-tethering compounds (ATTECs)-an innovative targeted protein degradation technology. Notably, MC-ND-18 emerged as the most potent agent for effectuating NLRP3 degradation through autophagic mechanisms and concurrently exhibited marked anti-inflammatory efficacy in mice model of dextran sulfate sodium (DSS)-induced colitis. Consequently, we have successfully developed a pioneering NLRP3 protein degrader, offering a novel therapeutic avenue for ameliorating NLRP3-associated pathologies.
Asunto(s)
Autofagia , Sulfato de Dextran , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Autofagia/efectos de los fármacos , Ratones , Humanos , Estructura Molecular , Relación Estructura-Actividad , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Inmunoterapia , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Proteolisis/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis químicaRESUMEN
Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.