Synthetic biology + medicinal chemistry

The Problem

Drug design is exceedingly difficult. Despite advances in computational chemistry and structural biology, approximately 90% of proteins in the human proteome remain “undruggable” (i.e., they lack an obvious pocket for a drug to bind), and over 50% contain disordered regions that preclude detailed crystallographic analysis. Today, many entire classes of proteins lack targeted therapeutics of any kind.

Prevailing Challenges

1.Limited Molecular Search Space

Most compound libraries contain molecules chosen for their synthetic accessibility or (historical) drug-like attributes. These compounds are biased to bind solvent-exposed regions, usually active sites, and struggle to find new druggable pockets.

2.Form Over Function

The industry is awash in powerful methods for finding footholds on proteins—fragment screens, DNA-encoded libraries, computational pocket finders. Unfortunately, most pockets are not functional and cannot support drug design.

3.Protein Motion

Proteins move, and their motion can uncover nonintuitive, functionally influential binding sites (e.g., a site distal to the active site of an enzyme). Functional cryptic pockets are promising starting points for drug development on difficult-to-drug targets, but they remain extremely difficult to find.

4.Complex Objectives

Small-molecule drugs can bind to one protein, multiple proteins, or an ensemble of functional states (e.g., “on” conformations); however, screens for molecules that achieve these precise biochemical feats remain difficult to carry out.

We engineer microbial systems to guide the development of small-molecule drugs with historically elusive properties.

Platform Advantages

Encoded Complexity

Design synthetic transcriptional circuits that detect focused, context-dependent biochemical activities.

Undruggable Targets

Incorporate challenging targets that lack crystal structures, sample multiple conformations, or contain disordered regions.

Molecular Diversity

Survey large genetically encoded libraries to find novel solutions to circuit-encoded challenges.

Differentiated Activity

Build molecules with unprecedented biochemical properties (selectivity, brain penetration, and beyond)

Targets of Interest

Protein Tyrosine Phosphatases

Protein Tyrosine Phosphatases

Protein tyrosine phosphatases (PTPs) catalyze the hydrolytic dephosphorylation of tyrosine residues and contribute to a striking variety of diseases (e.g., diabetes, cancer, autoimmunity, neurological disorders, deafness, and heart disease). Despite this contribution, there are no FDA-approved therapeutics that target PTPs.

Protein Tyrosine Kinase (PTK)

Protein Tyrosine Kinases

Protein tyrosine kinases (PTKs) catalyze the phosphorylation of tyrosine residues and regulate essentially all aspects of cellular function. Over 50 FDA-approved drugs target PTKs, but selectivity and brain penetration are still difficult to achieve. Many important PTK targets remain undrugged.

Transcription
Factors

Transcription factors regulate the transcription of DNA into RNA. Anomalously regulated—or assembled—transcription factors contribute to autoimmune diseases and several types of cancer. Although approximately 10% of prescribed drugs target the nuclear receptor class of TFs, most promising TF targets have no approved therapeutics.

Other Undruggable
Targets

Our platform is target-agnostic. We are drawn to difficult targets, particularly those with ill-defined (e.g., disordered) structures, suboptimal (e.g., charged) binding sites, or conditional deleterious effects.

Publications

Microbially Guided Discovery and Biosynthesis of Biologically Active Natural Products

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Evolution-Guided Biosynthesis of Terpenoid Inhibitors

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Genetically Encoded Detection of Biosynthetic Protease Inhibitors

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