RESUMEN
SARS-CoV-2 Omicron subvariants such as BA.2.12.1, BA.4 and BA.5 have been spreading rapidly and become dominant worldwide. Here we report the homologous or heterologous booster effects of S-268019-b, a recombinant spike protein vaccine with the squalene-based adjuvant A-910823 in cynomolgus macaques. In macaques which had been primed with S-268019-b or mRNA vaccines, boosting with S-268019-b enhanced neutralizing antibodies (NAb) against ancestral SARS-CoV-2. Since boosting with the antigen without adjuvant did not efficiently restore NAb titers, adjuvant A-910823 was essential for the booster effect. Importantly, boosting with S-268019-b enhanced NAb against all of the Omicron subvariants we tested, including BA.2.12.1, BA.4 and BA.5, in comparison to two vaccine doses. Additionally, expansion of Omicron-specific B cells was confirmed after boosting with S-268019-b. These results indicate that a booster dose of S-268019-b with the adjuvant enhances the neutralization breadth.
Asunto(s)
COVID-19 , Escualeno , Animales , SARS-CoV-2 , COVID-19/prevención & control , Vacunas Sintéticas/genética , Adyuvantes Inmunológicos , Macaca fascicularis , Anticuerpos Neutralizantes , VacunaciónRESUMEN
Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with development of insulin resistance. In particular, diacylglycerol and ceramide are currently considered as causal bioactive lipids for impaired insulin action. Recently, inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation, has been shown to reduce total IMCL content and improve whole-body insulin resistance. This study aimed to investigate whether ACC2 inhibition-induced compositional changes in bioactive lipids, especially diacylglycerol and ceramide, within skeletal muscle contribute to the improved insulin resistance. In skeletal muscle of normal rats, treatment of the ACC2 inhibitor compound 2e significantly decreased both diacylglycerol and ceramide levels while having no significant impact on other lipid metabolite levels. In skeletal muscle of Zucker diabetic fatty (ZDF) rats, which exhibited greater lipid accumulation than that of normal rats, compound 2e significantly decreased diacylglycerol and ceramide levels corresponding to reduced long chain acyl-CoA pools. Additionally, in the lipid metabolomics study, ZDF rats treated with compound 2e also showed improved diabetes-related metabolic disturbance, as reflected by delayed hyperinsulinemia as well as upregulated gene expression associated with diabetic conditions in skeletal muscle. These metabolic improvements were strongly correlated with the bioactive lipid reductions. Furthermore, long-term treatment of compound 2e markedly improved whole-body insulin resistance, attenuated hyperglycemia and delayed insulin secretion defect even at severe diabetic conditions. These findings suggest that ACC2 inhibition decreases diacylglycerol and ceramide accumulation within skeletal muscle by enhancing acyl-CoA breakdown, leading to attenuation of lipid-induced insulin resistance and subsequent diabetes progression.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Alquenos/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inhibidores Enzimáticos/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Músculo Esquelético/metabolismo , Acetilcoenzima A/efectos de los fármacos , Acetilcoenzima A/metabolismo , Alquenos/farmacocinética , Alquenos/uso terapéutico , Animales , Ceramidas/metabolismo , Correlación de Datos , Diglicéridos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Resistencia a la Insulina , Lípidos/análisis , Masculino , Oxidación-Reducción/efectos de los fármacos , Ratas Sprague-Dawley , Ratas Zucker , Triglicéridos/metabolismoRESUMEN
Invasive fungal infections (IFIs) are fatal infections, but treatment options are limited. The clinical efficacies of existing drugs are unsatisfactory because of side effects, drug-drug interaction, unfavorable pharmacokinetic profiles, and emerging drug-resistant fungi. Therefore, the development of antifungal drugs with a new mechanism is an urgent issue. Herein, we report novel aryl guanidine antifungal agents, which inhibit a novel target enzyme in the ergosterol biosynthesis pathway. Structure-activity relationship development and property optimization by reducing lipophilicity led to the discovery of 6h, which showed potent antifungal activity against Aspergillus fumigatus in the presence of serum, improved metabolic stability, and PK properties. In the murine systemic A. fumigatus infection model, 6h exhibited antifungal efficacy equivalent to voriconazole (1e). Furthermore, owing to the inhibition of a novel target in the ergosterol biosynthesis pathway, 6h showed antifungal activity against azole-resistant A. fumigatus.
Asunto(s)
Antifúngicos/farmacología , Ergosterol/antagonistas & inhibidores , Guanidina/farmacología , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Tiazoles/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Aspergillus fumigatus/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ergosterol/biosíntesis , Guanidina/análogos & derivados , Guanidina/química , Humanos , Infecciones Fúngicas Invasoras/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
Intramyocellular lipid (IMCL) accumulation in skeletal muscle greatly contributes to lipid-induced insulin resistance. Because acetyl-coenzyme A (CoA) carboxylase (ACC) 2 negatively modulates mitochondrial fatty acid oxidation (FAO) in skeletal muscle, ACC2 inhibition is expected to reduce IMCL via elevation of FAO and to attenuate insulin resistance. However, the concept of substrate competition suggests that enhanced FAO results in reduced glucose use because of an excessive acetyl-CoA pool in mitochondria. To identify how ACC2-regulated FAO affects IMCL accumulation and glucose metabolism, we generated ACC2 knockout (ACC2-/-) mice and investigated skeletal muscle metabolites associated with fatty acid and glucose metabolism, as well as whole-body glucose metabolism. ACC2-/- mice displayed higher capacity of glucose disposal at the whole-body levels. In skeletal muscle, ACC2-/- mice exhibited enhanced acylcarnitine formation and reduced IMCL levels without alteration in glycolytic intermediate levels. Notably, these changes were accompanied by decreased acetyl-CoA content and enhanced mitochondrial pathways related to acetyl-CoA metabolism, such as the acetylcarnitine production and tricarboxylic acid cycle. Furthermore, ACC2-/- mice exhibited lower levels of IMCL and acetyl-CoA even under HFD conditions and showed protection against HFD-induced insulin resistance. Our findings suggest that ACC2 deletion leads to IMCL reduction without suppressing glucose use via an elevation in acetyl-CoA metabolism even under HFD conditions and offer new mechanistic insight into the therapeutic potential of ACC2 inhibition on insulin resistance.