RESEARCH: CANCER
FOLDING PROJECT #12443 PROFILE

This project looks at how tiny proteins called peptides can block autophagy, a process where cells clean up waste. Blocking autophagy could make cancer cells more vulnerable to chemotherapy. Scientists are using computer simulations to design better peptides that stick tightly to their targets and work well in the body.

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 waste. It's also being studied as a potential target for cancer therapies because inhibiting its function can make cancer cells more sensitive to chemotherapy.

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Autophagy

The natural process of cellular degradation and recycling.

Autophagy is a vital process where cells break down and recycle their own components. This helps maintain cellular health, remove damaged parts, and provide energy during times of stress. It plays a crucial role in various biological processes, including development, immunity, and aging.

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Lysosomes

Cellular organelles responsible for breaking down waste materials.

Lysosomes are tiny compartments within cells that act like recycling centers. They contain powerful enzymes that break down various substances, including cellular debris, foreign invaders, and worn-out organelles. This process is essential for maintaining cellular health and removing harmful substances.

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Cancer Therapy

Treatment aimed at destroying or controlling cancer cells.

Cancer therapy encompasses various approaches to treat and manage cancer. These include surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapies. The goal of cancer therapy is to eliminate or control the growth of cancerous cells while minimizing harm to healthy tissues.

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Stapled Peptide Inhibitors

Molecules designed to bind and inhibit the function of specific proteins.

Stapled peptide inhibitors are a class of drugs that mimic natural peptides and target specific proteins involved in disease processes. They are designed to bind tightly to their target proteins, preventing them from functioning properly and halting the progression of the disease.

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LC3

Microtubule-associated protein 1 light chain 3

LC3 is a protein crucial for autophagy. It helps form structures called autophagosomes, which engulf cellular waste and deliver it to lysosomes for degradation.