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

Area of Science:

• Biochemistry
• Pharmacology
• Nephrology

Background:

• Impaired cellular cholesterol efflux contributes to renal, cardiovascular, and autoimmune diseases.
• Understanding cholesterol homeostasis is crucial for treating these conditions.

Purpose of the Study:

• To identify novel compounds that enhance cellular cholesterol efflux.
• To elucidate the molecular target and therapeutic potential of these compounds in kidney disease models.

Main Methods:

• Phenotypic drug discovery to identify 5-arylnicotinamide compounds.
• Chemical biology, including photoactivatable cross-linking and immunoprecipitation, to identify the molecular target.
• In vitro studies with podocytes and in vivo studies using mouse models of proteinuric kidney disease (Adriamycin nephropathy, Alport Syndrome).

Main Results:

• A class of 5-arylnicotinamide compounds was identified that upregulates ABCA1-dependent cholesterol efflux.
• Oxysterol Binding Protein Like 7 (OSBPL7) was identified as the molecular target of these compounds.
• Compounds Cpd A and Cpd G induced ABCA1 and cholesterol efflux in podocytes, normalized proteinuria, and prevented renal function decline in mouse models.

Conclusions:

• Small molecule drugs targeting OSBPL7 provide an alternative mechanism to upregulate ABCA1.
• Targeting OSBPL7 represents a promising therapeutic strategy for renal diseases.
• This approach may also benefit other disorders of cellular cholesterol homeostasis.