DC 10: Lead finding and structural characterization of the 5’-UTR of ompA of A. baumannii using fragment screening and application of paramagnetic NMR restraints

PhD project description:

First, we will apply the fragment-based NMR screening method to the 5’-UTR of ompA (at Saverna). For hit expansion, we will use AI methods developed at Saverna to select compounds from large combinatorial compound libraries which will subsequently be tested for binding to the target RNA. The same method will also be used to select follow-up compounds of fragment hits for the remaining targets in the network.

Second, we will determine the structure of 5’-UTR of ompA. The target consists of 131 nucleotides and contains several secondary structure elements. To determine the structure of such a large RNAs in solution by NMR spectroscopy we will develop new methods using paramagnetic restraints. This will also require to synthesize new paramagnetic tags and conjugate them to fragments and/or RNA to refine the RNA-ligand interactions. The obtained PCS will provide long-range (>100 Å) distance and angular restraints that will be very helpful in connecting the secondary structure elements and determine the overall 3D structure of the RNA.

Subsequently, we will probe the influence of ligands developed in WP2 on the dynamics of the target using NMR spectroscopy. We will also collaborate with DC14 on compound design for this target.

Research environment:

In both teaching and research the Department of Chemistry includes the whole breadth and thematic diversity of modern chemistry. In addition to the traditional three pillars of inorganic, organic and physical chemistry, the department has interdisciplinary foci in synthesis & catalysis, chemical biology, nanomaterials, and theoretical chemistry.

The Häussinger research group is a small (ca. 5 PhDs) group focusing on the design and synthesis of lanthanoid chelating tags for NMR applications in structural biology and offers an environment with a favourable student / advisor ratio.

Saverna Therapeutics is a small company in Basel, that was founded 2017 with a mission to change the way pharmaceutical companies discover and develop active pharmaceutical ingredients. Saverna Therapeutics aims to discover highly active, selective and cell-permeable low molecular weight molecules that target RNA biology.

Skills/qualifications:

The candidate must hold a MSc. degree in chemistry, molecular biology or closely related fields.

A strong background in synthetic organic chemistry and basic knowledge of solution NMR is required.

English language skills equivalent to C1 level are also expected.

We look forward to an intrinsically motivated, team-oriented person that is curious to learn a variety of techniques for a challenging and exciting project comprising advanced and computation assisted methods

Benefits/salary/social security:

The Basel area is one of the most productive and innovative economic regions in the world and home of numerous international chemical and pharmaceutical as well as biotech start-up companies. Located in the trinational region of Switzerland, Germany and France, Basel is a vibrant city with a very rich cultural life and pleasant mediterranean flair.

UB provides the obligatory social security i.e. 50% of the contributions to social security (AHV -retirement funds, SUVA - accident insurance, IV - invalidity insurance, EO - insurance against loss of salary due to illness, ALV - unemployment insurance) and a special retirement fund (Pensionskasse). Health insurance has to be paid by the employee (flat rate).

The University of Basel offers attractive salaries (152’245.80 CHF - total for 3 years) as well as help with onboarding and dealing with administrative requirements.

For more information about the position, please contact Daniel Häussinger.