PhD position in Chemical Biology

Bioactive peptide natural products are interesting leads for the development of pharmaceuticals as they (1) cover a huge chemical space due to their modular structure and (2) are, by their sheer size, able to cover a sufficient surface area on a protein to efficiently interfere with protein-protein interactions. In addition, these peptides often carry modifications of their amino acid side chains or their backbone that improve their pharmacokinetics e.g. provide passive membrane permeability to make them orally available and/or resistance to proteases to increase their retention time in the body.

In the course of our basic research on fungal peptide natural products, we discovered that omphalotin A, a ribosomally synthesized dodecapeptide macrocycle carrying multiple backbone N-methylations and displaying toxicity towards the root-knot nematode Meloidogyne incognita, also has immunomodulatory activity. This activity is reminiscent of cyclosporin A, a structurally related fungal peptide natural product, that was discovered as antifungal in the late 1970s and has been employed as blockbuster immunosuppressant in organ transplantations. The immunosuppressive activity of cyclosporin A is based on its passive membrane permeability and its binding to the cytoplasmic prolyl-cis/trans-isomerase cyclophilin and the protein phosphatase calcineurin. Based on the immunomodulatory activity of omphalotin A and its structural similarity to cyclosporin A, we hypothesize that omphalotin A targets a different, yet-to-be-identified intracellular protein of immune cells to exert its function.

We propose to identify, in a 4-year PhD project, the target protein of omphalotin A in immune cells using two different proteomics approaches. The results of the experiments will provide insight into the mode of action of an immunomodulatory fungal peptide natural product. This insight may potentially contribute to the development of a novel immunomodulatory drug, based on the omphalotin A scaffold or its target.

You are able to start on 1. May 2025, are an EU- or Swiss citizen with an MSc in Molecular Biology/Chemical Biology/Biological Chemistry and have a strong interest in the dissection of the mode of action of bioactive compounds at the molecular, cellular and organismal level. Experience in biotechnology, biochemistry and proteomics is desirable but not necessary.

We offer a guaranteed funding for 4 years, an excellent research infrastructure and a dynamic and international working atmosphere. You will be member of the PhD program 'Microbiology and Immunology' of the Life Science Zürich Graduate School with its support and networking program.