Aside from chemically synthesized compound libraries, natural products and secondary metabolites comprise a nearly indefinite resource of small molecules invented by nature and pre-optimized by evolution to have drug-like properties. Recent advances in high-throughput DNA sequencing and computational analysis suggest that the vast majority of natural products remain undiscovered. We use droplet microfluidics to mine the enormous diversity of metabolites derived from microorganisms that inhabit the human body, or from any other microbiota. 100 million parallel droplet cultures allow us to mine the diversity of the microbiota for chemical structures that are otherwise difficult to obtain. A unique feature of the microfluidic platform is its ability to culture the vast majority of the microbiota including previously unculturable microbes thereby ensuring unprecedented access to novel molecules and the biosynthetic gene clusters that encode them. Our access to live microorganisms helps us to decipher microorganism-host communication at scale in combination with our G-protein coupled receptor screening platform to rapidly identify high value, drug-like metabolites.

Our cell-based multiplex GPCR platform measures activity of ligands and not only receptor binding as our GPCR platform mines ligands from any source at unprecedented throughput compared to other technologies by multiplexing hundreds of bioassays in a single assay well. This also reduces the volumes of compounds required for screening by 1000x fold and allows us to test hit compounds for off-target effects on hundreds of GPCRs simultaneously. Following GPCR hit generation, our machine-learning expertise and cell-free biosynthetic molecule platform enables us to identify chemical functions of molecular pathways in silico at significant speed and scale and to re-validate them ex-vivo against the targeted GPCR receptors and their variants. Therefore, our discovery platform delivers drug candidates with unprecedented validation at an early stage.  These unparalleled properties of our platform also permit exploration of orphan GPCRs for yet unknown ligands of therapeutic potential as well as for profiling of global GPCR activity directly from patients’ samples.

We explore large multidimensional data sets along with identified chemical structures and biosynthetic pathways. Thousands of pairwise biological assay interactions are simultaneously tested to determine, e.g., binding specificity and dose-response readouts. Algorithm-guided mining of biosynthetic gene clusters and molecule families combined with DNA programming and cell-free biosynthetic compound synthesis turn around drug candidate compounds for testing faster than any traditional method. Our engineering-inspired “Design-Build-Test-Analyze” cycles enabled by our cell-free biosynthetic platform fuel machine learning to create better drug candidates more rapidly.

Design Pharma’s cell-free biosynthetic engineering approaches are used to access new chemical scaffolds and new enzymes capable of performing diverse chemistries. The mixture of such enzymes guided by biosynthetic gene clusters serve as flexible biocatalytic tools to further expand the unique chemical space of natural products, secondary metabolites and any other pharmacologically relevant chemical structures. Our platform eliminates the need for time-consuming re-engineering of live microorganisms that imposes inherent limitations on the effective synthesis and release of target products. Additionally, using cell-free synthetic biology reduces issues with toxicity of compounds and intermediates to live organisms and allows semisynthetic approaches to compound synthesis that are not feasible using live organism-based platforms. As the engineering-inspired rapid design-build-test cycles of pathway components are reduced to combinatorial high-throughput liquid handling, we have leveraged this platform to address the pain points in drug discovery and development and transform state-of-the-art approaches to compound synthesis and manufacturing to a highly scalable and high-throughput process. Hence, our platform allows for a rapid and streamlined process to biosynthesize identified hit compounds or known valuable pharmaceuticals and their optimization by creating diversified compound libraries.