Research and Thesis Projects

• Harnessing the power of directed evolution for drug development

Location: Bioprocess Laboratory, D-BSSE, ETH Zurich, Basel, Switzerland
Start: anytime, as soon as possible
Duration: 6-8 months
Contact: Liz Armas () or Martin Held ()

Over half a million intracellular protein-protein interactions (PPIs) are relevant to diseases such as cancer and neurodegenerative disorders. However, many PPIs are considered 'undruggable' due to the size of the interacting surfaces of the involved proteins. Small molecule drugs only cover a minimal fraction of the interaction surface, making it difficult for them to break PPIs. In contrast, protein-based drugs could have the potential to disrupt PPIs but face challenges when being delivered to their target cells or tissues. This gap can be bridged by peptides, which are large enough to cover a substantial portion of the interaction surface while also frequently being membrane permeable.
In this project, you will be developing a high-throughput screening platform for PPI-inhibiting peptides. For this, we will equip bacterial reporter cells with reverse two-hybrid systems (RTHS). In such systems, the disruption of a PPI can be detected through reporter genes linked to cell growth. By producing peptides from DNA libraries in E. coli cells that carry an RTHS, this system allows screening >1 million peptides per assay. The most potent peptides will then be identified by next-generation sequencing followed by validation experiments in vitro. As fundamental part of the project, we will implement iterative cycles of structure-based computational design and screening.

In this way, drug development can harness the power of directed evolution to gradually enhance the affinity of peptide ligands and increase their efficacy for PPI disruption.
To apply, please send us your CV together with a small paragraph telling us about your interests and relevant experience. Join our research team in Basel, Switzerland’s biotechnology hub, where you'll thrive in a stimulating lab environment surrounded by diverse talents from various countries and backgrounds.

Your main tasks during this project will include:
i. Assembling the bacterial reverse two-hybrid systems
ii. Computational design and screening of cyclic peptide libraries
iii. In vitro PPI modulation with selected cyclic peptides
Techniques you will practice include:
• Molecular cloning and genome editing
• Computational design of inhibitor libraries (AlphaFold2, Rosetta)
• Next-generation sequencing
• Fluorescence-activated cell sorting (FACS)
• Recombinant expression and purification of proteins in E. coli
• Isothermal titration calorimetry for detection of ligand-protein binding

• We have no other available projects at this time.

Please consult the research section on general topics and come by to discuss projects in detail or contact us via e-mail: