Official Project Description
GABARAP (gamma-aminobutyric acid receptor-associated protein) plays an important role in autophagy, the process by which cytosolic material is transported to cellular compartments called lysosomes for degradation.
It is also a target for cancer therapy: inhibiting the function of GABARAP can help sensitize cancer cells to chemotherapy.
The Kritzer lab at Tufts University has developed stapled peptide inhibitors of LC3 and GABARAP proteins (Brown et al.
2022).
We are using molecular simulation and free energy approaches to understand how peptide sequence and the staple linker chemistry control the affinity and selectivity of these peptide binders, both through their interactions at the protein surface, but also through the extent of peptide preorganization in solution.
Our long-term goal is to use these methods to improve the affinity and bioavailability of conformationally constrained peptides through N-methylation and other non-natural modifications. Reference Brown, Hawley, Mia Chung, Alina Üffing, Nefeli Batistatou, Tiffany Tsang, Samantha Doskocil, Weiqun Mao, et al.
“Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy.” Journal of the American Chemical Society 144, no.
32 (August 17, 2022): 14687–97.
https://doi.org/10.1021/jacs.2c04699.
.