RESEARCH: CANCER
FOLDING PROJECT #12444 PROFILE

This project looks at how tiny molecules can block a protein called GABARAP. This protein is involved in recycling parts of cells and might be a target for cancer treatment. Researchers are using computer simulations to design better molecules that can attach to GABARAP more effectively.

Note: This TLDR is a simplication and may not be 100% accurate.

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.

.

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GABARAP

gamma-aminobutyric acid receptor-associated protein

GABARAP is a protein involved in autophagy, the process of breaking down cellular material. It's also a target for cancer therapy, as inhibiting GABARAP can make cancer cells more sensitive to chemotherapy.

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Autophagy

The natural process of cellular degradation and recycling.

Autophagy is a crucial cellular process where old or damaged components are broken down and recycled. This helps maintain cell health and function. It's also involved in immune responses and protecting against disease.

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Lysosomes

Membrane-bound organelles within cells responsible for breaking down waste materials and cellular debris.

Lysosomes are like the recycling centers of cells. They contain enzymes that break down various substances, including worn-out organelles, engulfed bacteria, and cellular waste products.

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Cancer Therapy

Medical treatments aimed at preventing, controlling, or curing cancer.

Cancer therapy encompasses various approaches to treat cancer, including surgery, chemotherapy, radiation therapy, and immunotherapy. The goal is to eliminate or control cancerous cells while minimizing harm to healthy tissues.

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Stapled Peptides

A type of synthetic peptide stabilized by a covalent bond between two amino acids.

Stapled peptides are engineered proteins designed to be more stable and have improved binding properties. They are being explored as potential therapeutics due to their ability to target specific proteins.

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Molecular Simulation

Computer-based modeling and analysis of molecular systems.

Molecular simulation uses computational techniques to simulate the behavior of molecules and their interactions. This helps researchers understand complex biological processes and design new drugs and materials.

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Free Energy Approaches

Methods used to calculate the thermodynamic stability of molecular systems.

Free energy approaches are computational techniques used to determine the stability and feasibility of chemical reactions and molecular interactions. This information is essential for drug design and understanding biological processes.

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N-Methylation

The addition of a methyl group to the nitrogen atom of an amino acid.

N-methylation is a common chemical modification used in drug development to alter the properties and activity of molecules. It can affect solubility, stability, and target binding.