Stapled peptides inhibitors: a new window for target drug discovery
|PhD ceremony:||Ms A. (Amina) Ali|
|When:||March 22, 2019|
|Supervisors:||prof. dr. A.S.S. (Alexander) Dömling, S.K. Goda|
|Where:||Academy building RUG|
|Faculty:||Science and Engineering|
Amina Ali successfully produced stable and correctly refolded proteins as an approach for structural and biophysical studies. Drug target studies elucidated the core role of protein-protein interaction (PPI) in human disease processes, making them very interesting targets for modulation with inhibitors. These agents are generally classified as either small molecules or biologics; with each class having different pharmacological properties and limitations.
Recently, a new class has emerged to target intracellular PPIs that are not otherwise addressable, namely peptides. All-hydrocarbon stapled peptides retain an excellent recognition surface to the target with minimal toxicity and overcome limitations of native peptides. This was applied in the PPI research target of Ali: p53-MDM2, to develop novel strategies to treat cancer. In addition to introducing the multicomponent reaction (MCR) technique as a potent method in staple synthesis, she is the first to apply the Microscale thermophoresis (MST) technique to investigate stapled peptides binding affinities toward MDM2. Her study generated three novel co-crystal structures of stapled peptides in complex with mutant MDM2 to reveal their mode of binding. Additionally, Ali solved Pex4p:Pex22p complex structure as a novel PPI from the yeast Hansenula polymorpha to elucidate the role of the PPI in peroxisomal recycling. PPIs rely on interactions at specific surface area and topology, and their examination using biophysical techniques requires the production of pure target protein. Thus, li has also developed a refolding buffer screening system to determine the correct refolding conditions in cost-effective, reliable and time saving manner using differential scanning fluorimetry (DSF).