European Fellowships

ESR 3

Developing prebiotic iron-sulfide peptide catalysts

Host institution

 University of Trento, Department CIBIO

Supervisor:

 Sheref S. Mansy

Objectives:

1) To identify prebiotically plausible short peptide sequences that coordinate a [4Fe-4S] cluster that is capable of binding carboxylate containing substrates,
2) to integrate enzyme-like [4Fe-4S] peptides within protometabolic networks, 
3) to elucidate metal-dependent mechanisms for the generation of protein-like sequences from prebiotic peptides.

Description:

Metal ions are important for extant and prebiotic metabolic-like chemistry with some pathways, e.g. the citric acid cycle, requiring more complex metallocofactors, such as iron-sulfur clusters. We recently demonstrated that tripeptides can stabilize the formation of redox active iron-sulfur clusters under prebiotically plausible conditions and can help generate pH gradients across protocell membranes. However, short iron-sulfur peptides have yet to be tested for enzyme-like activity. The ESR will synthesize iron- sulfur peptides capable of catalyzing steps of the citric acid cycle that are dependent upon the [4Fe-4S] protein aconitase. The [4Fe-4S] cluster of aconitase directly coordinates the substrate citrate or isocitrate, catalyzing a stereo-specific isomerization reaction through a dehydration-rehydration mechanism that forms aconitate as an intermediate. The ESR will use NMR, paramagnetic NMR, Mössbauer, and GC-MS measurements to assess activity. The ESR will spend time in the laboratories of collaborators, including those of Matthew Powner (University College London), Joseph Moran (University of Strasbourg), and the company Metallopharm (USA), in addition to participating in international meetings and workshops.

Expected Results:

(1) First example of enzyme-like activity from prebiotic metallopeptides, (2) insight into the origin of extant enzyme sequences, (3) thorough training in prebiotic chemistry and bioinorganic chemistry, (4) securement of an excellent postdoctoral position.

Profile of the fellow:

The ideal candidate will have a MS or equivalent degree in chemistry or related field, have experience working with metal ions, and have a strong interest in the origins of life, although all excellent candidates regardless of specialization will be considered. The ESR will work with several collaborators and so an ability to work in a team and a willingness to travel is a must. Proficiency in English is required.

How to apply

Full description of the position and instructions for the application are  available at the link:

https://www.unitn.it/en/ateneo/bando/55120/department-cibio-call-for-the-selections-for-the-awarding-of-no-1-research-fellowship-for-the-covera

Deadline for application

 8th February 2019

Date of recruitment

 April 2019

ESR 3

Annotating and overcoming resistance to NAMPT inhibitors in cancer cells

Host institution

University of Trento, Department CIBIO

Supervisor:

Alessandro Provenzani

Objectives:

(1) To identify the molecular alterations leading to acquired resistance to NAMPT inhibitors identifying new vulnerabilities, (2) to select new drugs combination to reduce the risk of insurgence of drug resistance, (3) to elucidate the role of NAMPT and NAD producing/degrading enzymes to acquired resistance to anticancer agents (4) to dissect the role of extracellular NAMPT within extracellular vescicles vs secreted extracellular NAMPT.

Description:

The reaction mediated by NAMPT is the rate-limiting step in the synthesis of NAD from nicotinamide and NAMPT inhibitors hold potential for effective therapeutic agents. We recently demonstrated that acquired resistance to NAMPT inhibitors is due to the acquisition of skewed metabolic profiles characterized by increased glycolysis and increased tryptophan and glutamine utilization. The genetic mechanisms of pharmacoresistance are different according to the different cell lines (breast and leukemia) but converge to increase lactate dehydrogenase (LDH) activity. Accordingly, LDH inhibition with commercially available reagents effectively reverses resistance to the NAMPT inhibitor. The ESR will fully characterize the genetic and metabolic alterations of further cancer cell models resistant to NAMPT inhibitors (prostate and pancreatic cancer cells as not limiting examples),  and identify new combinations of targeted agents to overcome acquired resistance to NAMPT inhibitors via combinatorial drug screening. The ESR will also be involved in the design, synthesis and evaluation of antibodies conjugated with innovative anticancer agents. In addition, The ESR will assess the presence of NAD producing/degrading enzyme in extracellular vesicles and their role in cancer progression and drug-resitance.

The ESR will spend time in the laboratories of collaborators and companies as Innovamol and Heidelberg Pharma, in addition to participating in international meetings and workshops.

Expected Results:

(1) Identification of vulnerabilities in cancer cells resistant to NAMPT inhibitors, (2) Elucidation of the molecular mechanism leading to acquired resistance to NAMPT inhibitors, (3) design and utilization of new anticancer agents, (4) elucidation of the role of NAD producing/degrading enzyme in extracellular vescicles; 5) To engineer EVs as anti-neoplastic agent.

Profile of the fellow:

The ideal candidate will have a MS or equivalent degree in Biology, Biotechnology, Pharmaceutical Chemistry or related field, have experience working with cancer cell culturing and characterization and cancer pharmacology have a strong interest in the cancer metabolism and molecular biology of cancer cells, although all excellent candidates regardless of specialization will be considered. The ESR will work with several collaborators and so an ability to work in a team and a willingness to travel is a must. Proficiency in English is required.

How to apply

Full description of the position and instructions for the application are available at the link:

https://www.unitn.it/en/ateneo/bando/55848/department-cibio-call-for-the-selections-for-the-awarding-of-no-1-research-fellowship-for-the-covera

Deadline for application

28th February 2019

Date of recruitment

April 2019