ESR 15: High throughput screening of small molecule inhibitors of CLEC-2

Host: Universidad de Santiago de Compostela, Spain

Supervisory team: Ángel García (University of Santiago, Spain); Steve Watson and Mike Tomlinson (University of Birmingham, UK)

Project locations: University of Santiago de Compostela (Year 1 and 2); Pivot Park (2 months); University of Birmingham (Year 2 and 3)

Joint PhD Degree: University of Santiago and University of Birmingham

Project details: C-type lectin-like receptor 2 (CLEC-2) elicits powerful platelet activation upon engagement by its endogenous ligand, podoplanin. Podoplanin is expressed on the surface of tumour cells and facilitates tumour metastasis by inducing platelet activation by CLEC-2. It is also expressed on certain normal cells, notably lymphatic endothelial cells where it is required for the separation of blood and lymphatic vessels during development.  CLEC-2 is involved in thrombus stabilization under flow conditions. Moreover, it promotes venous thrombosis during inflammation, including deep vein thrombosis.

We hypothesize that CLEC-2 may be a good target for novel anti-platelet drugs having therapeutic effects on arterial and venous thrombosis and cancer. The present PhD project aims to identify novel inhibitors of CLEC-2 on platelets. To do so, a platelet high throughput screening (HTS) assay will be set up for small molecules and nanobodies. An in-silico docking assay will be done for CLEC-2 using the chemical library available at Santiago. Nanobodies, generated against human CLEC-2, will also be tested. HTS assays will be carried out and potential hits selected and validated in functional and pharmacological assays to identify lead compounds. Lead compounds identified at Santiago will be further validated in Birmingham to investigate platelet function, focusing on the mechanism of CLEC-2 inhibition.

Desirable student skills: Biochemistry, Pharmacology, Molecular Biology.

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