Upgrading Biology with Chemistry
Our understanding of the complex, molecular processes in living organisms is at a level that seemed unimaginable only decades ago. Courtesy of the efforts that enabled this unprecedented insight, we have a powerful arsenal of tools at our disposal, which allows for probing and manipulating the structures and functions of the very building blocks that make up life. Access to this vast toolset makes chemists and biologists uniquely equipped to become engineers to facilitate man-made innovations. Pursuing this enticing concept, we aim to chemically upgrade (1) cellular factories that enable the production of value-added molecules and (2) peptide libraries to identify new lead compounds for therapeutic interventions.
Making cellular factories to order
Imagine a world in which biocatalysts in microbes and synthetic catalysts work alongside to produce value-added compounds from biomass or degrade pollutants on-demand (Scheme 1A). In such cellular factories, synthetic catalysts would perform new-to-nature transformations on molecules, which are provided by biocatalysts in designer microbes. But how can we identify synthetic catalysts that can function in concert with cells and fine-tune biocatalysts in microbes that produce molecules of no apparent use for an organism? To meet these challenges, we create biosensors that enable both the discovery of biocompatible small-molecule catalysts and the optimization of biotechnologically-relevant enzymes. These biosensors are based on the incorporation of non-canonical amino acids into proteins that give rise to a selectable phenotype, such as an optical readout or survival.
Better drugs by evolution
Organisms protect themselves in a competitive environment by a collection of exotic chemical weapons, evolved to attack the weak points of their competitors. For example, macrocyclic peptides (MPs), such as the antibiotic vancomycin, are the result of evolutionary algorithms that fine-tuned both the amino acids sequence as well as posttranslational processes for cyclizations or the introduction of non-peptidic moieties. We mimic such natural products by developing strategies for the generation and selection of chemically-upgraded MPs. For the upgrade, we employ modified privileged scaffolds – those are common building blocks for constructing small-molecule libraries – as non-peptidic cyclization units on the surface of bacteriophages. This strategy enables us to generate billions of natural-product-like MPs simultaneously and select binders that combine favorable traits of small-molecule and peptide-based drugs by phage display.