Ultra-deep exploration of drug-like molecules from natural product sources for GPCR targets

The Science and Technology behind Design Pharma

Natural product molecules offer advantages over traditional chemical libraries or biologics in drug discovery because they are usually orally available, are often cell-penetrating or can be appropriately modified, have good biologic distribution, and offer more diverse target binding options.

This makes natural drug-like molecules ideal as potential ligands or antagonists for G-protein coupled receptors (GPCRs), the single drug target class with the most FDA approvals for therapeutics. It is estimated that GPCRs are targets for approximately 50% of currently marketed drugs, primarily because they are involved in signaling pathways related to many diseases, e.g. mental, metabolic, inflammatory, immunological, cardiovascular disorders, and cancer.?

GPCRs are receptors with seven-(pass)-transmembrane domains and form a large group of cell surface receptors that are evolutionarily related and recognize molecules outside the cell and activate cellular responses. Ligands bind to the extracellular N-terminus or to binding sites within transmembrane helices, which is another reason why small molecules are generally better suited than large antibodies to target GPCRs as therapeutics.

Numerous publications have shown that the human microbiota is a rich source for the production of metabolites that can serve as ligands for GPCRs (e.g. the publication in Cell by Design Pharma's co-founder Noah Palm: A Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology, Cell (2019), https://doi.org/10.1016/j.cell.2019.03.036). In a previous post, we described Design Pharma's unique capabilities to link the metabolome of the human microbiota to bacterial genomes and biosynthetic gene clusters using microfluidics-based hundreds of millions bacterial single cell cultures (https://www.dhirubhai.net/pulse/missing-link-single-cell-culture-human-microbiota-/?trackingId=MF%2B88W%2FhuBbdH7nZoD1qIA%3D%3D).

Design Pharma is probing the metabolome for bioactive drug-like molecules using a modified version of the GPCR assay that we call PRESTO-SALSA and that does not rely on light or fluorescence as indicators of ligand-receptor binding, but instead uses the unprecedented scalability of next generation sequencing as a read-out method.

The PRESTO-SALSO platform provides us with the fastest and most comprehensive GPCR ligand discovery screens available to date based on activity assays. The use of next generation sequencing instead of light-based readout methods enables simultaneous multiplexing of more than 300 GPCR-encoding cell lines, reducing time of screening campaigns and reducing compound requirements by 1000-fold.?The tremendous throughput enables measurement of dose-response relationships early in the screening process, providing more reliable information about molecules that bind to a receptor as potential hit candidates. The heat map in the figure above shows the potential to test literally thousands of interactions simultaneously, providing additional information on the selectivity and off-target binding of candidate ligands. Because the platform requires minimal sample input, it is also ideal for direct screening of biological samples, such as precious patient samples or culture supernatants from Design Pharma's proprietary human microbiota cell bank for drug discovery.

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