Principal Investigator (PI)
The Foundation is providing £131,069 in support.
Imene Belhaouane
This project will benefit greatly from the considerable HTS capabilities of GSK. Additionally, it is expected the following contributions from GSK will support the project:
1) The availability of a large library of chemicals.
2) Chemistry support to select diversity set, hit compound selection and SAR.
3) Cytotoxicity, intra and extracellular assays to define the value of identified compounds.
4) Image analysis support.
5) The significant experience and proficiency in drug discovery using HTS screens.
6) The availability of established techniques to generate induced pluripotent stem cell (iPSC)-derived macrophages and infect Mtb.
HDTs isolated from the proposed project will enhance the intracellular killing of mycobacteria by targeting autophagy via the use/amplification of the host defence mechanisms. Such an outcome offers numerous beneficial effects.
These benefits include reducing cytotoxicity caused by current lengthy antimycobacterial treatment regimens, slowing or circumventing the development of multidrug strains, significantly increased the sterilizing efficacy of the first-line regimen, and shorting the antibiotic treatment duration for mycobacteria when used with TB antibiotics 2-6. Since it has been shown that co-administration of rapamycin (autophagy inducing chemical) with BCG vaccine enhanced Th1 immunity 9,10, it is proposed that HDT-mediated increases in Th1 responses also offers a novel strategy to improve vaccine efficacy through regulation of immunity.
This screen will also fill some gaps in our understanding of the critical autophagy. Thus, we can capitalize on prior knowledge and deliver novel therapies to patients and reduce drug development and registration time.