Abstract
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.
Highlights
Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases
We have shown that genetic overexpression of ABCA1 rescues mice from focal segmental glomerulosclerosis (FSGS)-type glomerulosclerosis[14], and that podocyte-specific ABCA1 deficiency worsens experimental DKD7
We describe the results of a phenotypic drug discovery (PDD) initiative that led to the identification of a class of small molecule inducers of ABCA1 (5-arylnicotinamides)
Summary
Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. These data suggest alternative approaches to upregulate ABCA1mediated cholesterol efflux may offer effective treatments for FSGS and other renal diseases Prior compounds, such as T1317 and GW3965, agonists of the liver-X-receptors (LXR), were shown to significantly induce ABCA1 mRNA expression and promote cellular cholesterol efflux to lipoproteins[15,16,17]. Efficacy testing in mouse models of proteinuric kidney disease (adriamycin-induced nephropathy and Alport syndrome) revealed that Cpds A and G normalize proteinuria, and significantly reduce renal fibrosis and renal functional decline These results show that small molecule drugs that target OSBPL7 offer an alternative approach to upregulate ABCA1 activity, and may represent an effective, safe new therapeutic strategy for the treatment of renal diseases
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