Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease

作者：M. Wright, Javier Varona Santos, C. Kemmer, C. Maugeais, J. Carralot, S. Roever, J. Molina, G. Ducasa, A. Mitrofanova, A. Sloan, Anis Ahmad, C. Pedigo, M. Ge, J. Pressly, L. Barisoni, A. Mendez, Jacopo Sgrignani, A. Cavalli, S. Merscher, M. Prunotto, A. Fornoni · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-24890-3 · 被引用次数：47 · 研究领域：Medicine

Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis. This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.