Synthesis of Tumour Targeting Conjugates for the Delivery of Splice-Switching Anti-cancer Agents at University of Strathclyde on FindAPhD.com

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Prof Glenn Burley, Prof S Mackay No more applications being accepted Funded PhD Project (Students Worldwide)

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Glasgow United Kingdom Molecular Biology Organic Chemistry Structural Biology Synthetic Chemistry

About the Project

Background

Alternative RNA splicing is an extraordinary process that generates proteomic diversity (estimated at up to 150,000 human proteins) from only 20,000 human genes. More than 90% of human genes use splicing to produce on average multiple protein isoforms, sometimes with antagonistic functions, to be expressed from a single gene. However, mutations affecting splicing can result in the onset of disease such as cancer. A prominent example is the aberrant splicing of the Bcl-X gene which is an apoptotic checkpoint. Bcl-x pre-mRNA encodes two isoforms with antagonistic functions. The major protein isoform (Bcl-xL) displays anti-apoptotic functions and is overexpressed in most cancer cells. Overexpression of the alternative protein isoform (Bcl-xS) results in caspase-mediated apoptotic cell death.

We have recently identified a small molecule (GQC-05) which induces a switch in Bcl-X splicing towards the pro-apoptotic Bcl-xS pre-mRNA isoform. Whilst GQC-05 displays potent anti-cancer in live cells, the ability to delivery these safely and effectively in vivo is required for therapeutic applications.

Project objective

The overall objective of this collaborative PhD studentship is to develop synthetic methodology to prepare tumour targeting peptide conjugates of GQC-05 and next-generation analogues. This will involve the development of new synthetic methodology to establish structure-activity-relationship profiling of GQC-05 for G-quadruplex targets guided by our structural biology collaborator Professor Guang Zhu (Hong Kong University of Science & Technology)

The specific aims of the studentship are:

(i) Establish a structure-activity-relationship (SAR) profile of GQC-05 using a range of biophysical and biochemical assays and structural biological studies.

(ii) Optimise synthetic methodology to prepare tumour targeting conjugates of GQC-05.

(iii) Identify optimal candidates for analysis in live cells.

Academic Environments

The student will receive unparalleled training in medicinal chemistry and nucleic acid chemical biology based in Strathclyde. In addition, the student will have the opportunity to travel to HKUST and spend time in Professor Zhu’s research group and learn techniques ranging from structural biology (NMR and X-ray crystallography, Cryo-EM) through to conducting cell-based assays.

Funding Notes

This is a 3.5-year studentship available to home students and includes stipend and fees. For international students, please contact Glenn Burley to explore eligibility. The student undertaking this project will form part of a strategic collaboration (i.e., one student based in Strathclyde and one in HKUST) between the groups of Professor Glenn Burley (Pure & Applied Chemistry) and Simon Mackay (Strathclyde Institute of Pharmacy & Biomedical Sciences), and Professor Guang Zhu (Hong Kong Institute of Science and Technology, HKUST).

References

1. Taladriz-Sender, A.; Campbell, E.; Burley, G.A. “Splice switching small molecules: a new therapeutic approach to modulate gene expression” Methods, 2019, 167, 134.
2. Weldon. C.; Behm-Ansmant. I.; Hurley. L.H.; Burley. G.A.; Branlant. C.; Eperon. I.C.; Dominguez. C. "Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X" Nucleic Acids Research, 2018, 46, 886.
3. Jobbins, A.M.; Reichenbach, L.F.; Lucas, C.M.; Hudson, A.J.; Burley. G.A.; Eperon. I.C. “The mechanisms of a mammalian splicing enhancer” Nucleic Acid Research, 2018, 46, 2145.
4. Weldon, C.; Behm-Ansmant, I.; Hurley, L.H.; Burley, G.A.; Branlant, C.; Eperon, I.C.; Dominguez, C. "Identification of G-quadruplexes in functional RNAs using FOLDeR" Nature Chemical Biology, 2016, 13, 18.
5. Geng, Y.; Liu, C.; Cai, Q.; Luo, Z.; Miao, H.; Shi, X.; Xu, N.; Fung, C. P.; Choy, T. T.; Yan, B.; Li, N.; Qian, P.; Zhou, B.; Zhu, G., Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence, Nucleic Acids Research 2021, 49, 5881.