Using microbes to build better medicines

The Challenge

Despite advances in computational chemistry and structural biology, drug design remains exceedingly difficult. 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. As a result of these challenges, many entire classes of important proteins lack targeted therapeutics of any kind.

Prevailing Challenges

1.Limited Molecular Search Space

Many compound libraries include molecules chosen for their synthetic accessibility, drug-like attributes (Lipinski's rule of five), or historical origin. Many molecular trajectories remain unexplored simply because they’re different.

2.Protein Motion

Proteins move, and their motion can reveal hidden sites that allow small molecules to control protein function from nonintuitive positions (e.g., a site distal to the active site of an enzyme). These sites, which are promising starting points for drug development, are challenging to find with existing biophysical methods.

3.Complex
Objectives

Small-molecule drugs can function by binding to a single protein, multiple proteins, or, perhaps, a protein in a special biophysical state. Screens for molecules that achieve these multifaceted objectives are challenging to assemble.

4.Scale Up

Once discovered, promising molecules must be synthesized in quantities sufficient for biochemical analysis, optimization, formulation, and clinical evaluation. For many interesting molecules, this synthesis is time-consuming and expensive.

Think Bioscience is using synthetic biology to address these challenges. With the aid of engineered microbial systems, we are developing therapeutics against elusive targets.

Platform Advantages

Molecular Diversity

Use biosynthetic machinery to explore a novel molecular search space in drug discovery.

Undruggable Targets

Discover small-molecule modulators of proteins that lack crystal structures, sample multiple conformations, or contain highly disordered regions.

Encoded Complexity

Design microbial systems to find bioactive compounds with improved efficacy and specificity.

Rapid Scale Up

Generate large quantities of promising molecules through simple fermentation.

Targets of Interest

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, regulating essentially all aspects of cellular function, and contributing to virtually every major therapeutic area. Although there are over 50 FDA-approved drugs that target PTKs, a substantial number of PTKs have not yet been drugged while new drug-resistant mutants continue to arise.

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

An allosteric inhibitor of protein tyrosine phosphatase 1B (PTP1B) was discovered. PTP1B is an elusive therapeutic target for the treatment of diabetes, cancer, and more recently implicated as an intracellular checkpoint. Findings illustrate the potential for microbes to discover and build natural products that exhibit precisely defined biochemical activities yet possess unexpected structures and/or binding sites.

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Evolution-Guided Biosynthesis of Terpenoid Inhibitors

Terpenoids are the largest and most structurally diverse group of natural products. Despite their well-documented biochemical versatility, the evolutionary processes that generate new functional terpenoids are poorly understood and difficult to recapitulate in engineered systems. In collaboration with CU Boulder, Think Bioscience demonstrates the use of a human drug target (PTP1B) as a synthetic biochemical objective to evolve a terpene synthase to produce enzyme inhibitors. Findings suggest that the plasticity of terpenes synthesis enables an efficient sampling of structurally distinct starting points for building new functional molecules and application in activity-guided screens.

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Genetically Encoded Detection of Biosynthetic Protease Inhibitors

Following proof-of-concept work in protein tyrosine phosphates, Think Bioscience in collaboration with CU Boulder demonstrates the ability to expand the microbial discovery platform into a new human drug target class (proteases). A bacterial two-hybrid (B2H) designed to detect the inactivation of the main protease of severe acute respiratory syndrome coronavirus 2 enabled the identification of a terpenoid inhibitor of modest potency. This study provides a detailed experimental framework for using microbes to screen libraries of biosynthetic pathways for targeted protease inhibitors.

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