Selection of Leptin Surrogates by a General Phenotypic Screening Method for Receptor Agonists

TL;DR

Scientists developed a new screening method to find biomolecules that mimic the effects of leptin, a hormone involved in regulating appetite and metabolism.

Contribution

The study introduces BRADS, a novel phenotypic screening method for identifying receptor agonist surrogates efficiently.

Findings

BRADS successfully identified a leptin surrogate in two weeks without specialized equipment.

The leptin surrogate mimics native leptin activity in cell assays.

BRADS is suggested to be applicable to other receptors like Notch and GPCRs.

Abstract

There is a high demand for agonist biomolecules such as cytokine surrogates in both biological and medicinal research fields. These are typically sourced through natural ligand engineering or affinity-based screening, followed by individual functional validation. However, efficient screening methods for identifying rare hits within immense libraries are very limited. In this research article, we introduce a phenotypic screening method utilizing biological receptor activation-dependent cell survival (BRADS). This method offers a high-throughput, low-background, and cost-effective approach that can be implemented in virtually any biochemical laboratory setting. As a proof-of-concept, we successfully identified a surrogate for human leptin following a two-week cell culture process, without the need for specialized high-throughput equipment or reagents. This surrogate effectively emulates the activity of native human leptin in cell validation assays. Our findings not only underscore the effectiveness of BRADS but also suggest its potential applicability to a broad range of biological receptors, including Notch and GPCRs.

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