The main goal of this proposal is to identify novel agonists of human FFAR1 and FFAR4 by systematic high throughput screening (HTS) of a comprehensive commercially available FDA-approved drug library. We intend to acquire a library containing more than 1000 FDA-approved drugs. Several vendors offer such libraries at different prices depending on the content of the library. The expected outcome of the proposed project is a proof-of-principle validation of already approved drugs as novel agents for the treatment of T2D through the activation of
the validated FFAR1 and FFAR4. The goal of the proposed project entails a state-of-the-art reverse pharmacology strategy which has been successfully by us in the past to identify modulators of known or orphan GPCRs.

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Objective 1 Development of a functional assay suitable for screening FDA-approved library on human FFAR1 and FFAR4 - Completed

 

Objective 2 HTS screening of the FDA-approved library on heterologously expressed human FFAR1 and FFAR4 followed by the identification of lead compounds with agonistic properties - Completed

 

Objective 3 Pharmacological profiling of the lead compounds, including determination of their potencies (EC50), efficacies (Emax) and specificity among other related FFA receptors (FFAR1, FFAR2, FFAR3 and FFAR4) to select only lead compounds with specific effects only on FFAR1, FFAR4 or on both - Completed

 

Objective 4 Determination of the lead compound effects on GSIS from EndoC-βH1 human insulinoma β-cells in 2D culture - Completed