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1.
Cell ; 175(2): 514-529.e20, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30220461

RESUMEN

The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.


Asunto(s)
HDL-Colesterol/metabolismo , Proteínas de la Membrana/fisiología , Proteínas de la Membrana/ultraestructura , Células 3T3 , Animales , Transporte Biológico/fisiología , Antígenos CD36/metabolismo , Células CHO , Proteínas Portadoras/metabolismo , Línea Celular , Membrana Celular/metabolismo , Membrana Celular/fisiología , Colesterol/metabolismo , Cricetulus , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/fisiología , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Membranas Mitocondriales/metabolismo , Alineación de Secuencia , Esteroles/metabolismo
2.
Bioorg Med Chem Lett ; 25(8): 1688-1691, 2015 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-25804718

RESUMEN

We evaluated the effect of combining 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE), a 2'-cationic modification, with a 2',4'-constrained 2'-O-ethyl nucleic acid (cEt BNA) on the activity of an antisense oligonucleotide (ASO) using PTEN as a model target. Our results suggest that replacing one cEt BNA nucleotide with 2'-O-DMAEOE nucleotide at the 5'-end of a 2-10-2 gapmer ASO maintained the potency relative to parent ASO in liver. The cationic 2'-O-DMAEOE modification did not improve the activity of ASO in extra-hepatic tissues. Results from this study provide guidance to design improved antisense oligonucleotide drugs.


Asunto(s)
Etano/análogos & derivados , Éteres/química , Ácidos Nucleicos/química , Oligonucleótidos Antisentido/química , Animales , Línea Celular , Etano/química , Hígado/metabolismo , Ratones , Oligonucleótidos Antisentido/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatos/química , ARN Mensajero/química , ARN Mensajero/metabolismo , Temperatura de Transición
3.
Clin Transl Sci ; 16(4): 575-580, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36631935

RESUMEN

This analysis sought to assess the clinical predictivity of an in vitro assay which utilized the human B-lymphoma BJAB cell line, for identification of antisense oligonucleotides (ASOs) with the potential to elicit innate immune activation in humans. Adverse events (AEs) from clinical trial data were analyzed based on prior clinical knowledge and network analysis of the clinical data to identify correlations with the BJAB assay. Clinically evaluated ASOs were ranked by the BJAB assay's mean log-fold increase in TNF expression levels. Flu-like reactions (FLRs) and injection site reactions (ISRs), were chosen as AEs of interest, along with those Medical Dictionary for Regulatory Activities preferred terms identified using AE network analysis. Fifteen different 2'-O-methoxyethyl (2'MOE) modified ASOs were ranked by the incidence of each AE group in the integrated safety data from 35 clinical trials. ISRs are considered to be local to the injection site, whereas FLRs are reflected by systemic constitutional symptoms. The correlations identified in this analysis of integrated clinical data provide evidence that the ASO sequences selected by the BJAB assay have a lower likelihood of causing systemic inflammatory AEs associated with FLRs, but not ISRs.


Asunto(s)
Oligonucleótidos Antisentido , Humanos , Oligonucleótidos Antisentido/efectos adversos , Línea Celular
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