Controlling apoptosis with computationally designed inhibitors targeting pro-survival and pro-apoptosis BCL2 family members
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BCL2 family proteins regulate apoptosis and thus play a critical role in tissue homeostasis and development in healthy cells. A number of pathologies exploit the BCL2 family to promote artificially prolonged life or premature death. The doctoral research presented here has employed computational protein design and in vitro evolution to create inhibitors with high affinity and specificity for each of the eight multi-domain pro-survival and proapoptotic BCL2 homologs, including the first-ever specific inhibitors for Bcl-w, Bcl-B, Bak and Bax. Inhibitors targeting pro-survival BCL2 proteins have been used to determine the unique BCL2 profiles of a variety of cancers, elucidating which homologs are most critical for survival and therefore identifying prime therapeutic targets. Inhibitors targeting pro-apoptotic BCL2 proteins are used in continuing work to improve gene editing efficiency in notoriously delicate hematopoietic stem cells and more broadly as a selection tool for other human cell engineering applications. This suite of high affinity protein inhibitors can furthermore be used to study apoptosis in normal and pathological biology, with advantages of spatiotemporal control and specific inhibition at the protein level compared to gene knock-out or knock-down approaches. More generally, this work shows that designed inhibitors can be generated for each member of a protein family with high structural similarity to probe the importance of specific protein-protein interactions in complex biological processes.
- Bioengineering