RESEARCH: CANCER
FOLDING PROJECT #12436 PROFILE

This project investigates how small proteins called peptides can block autophagy, a cellular recycling process. By tweaking the design of these peptides, scientists hope to develop new cancer treatments that make tumors more vulnerable to chemotherapy. They're using computer simulations to understand how different peptide structures interact with target proteins and enhance their effectiveness.

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 being studied as a target for cancer therapy because inhibiting GABARAP can make cancer cells more sensitive to chemotherapy.

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Autophagy

The natural process of cells degrading and recycling their own components.

Autophagy is a crucial cellular process where damaged or unnecessary parts are broken down and recycled. This helps maintain cell health and is involved in various processes like nutrient sensing and defense against infection.

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Lysosomes

Organelles within cells responsible for breaking down waste materials and cellular debris.

Lysosomes are like the cell's recycling centers. They contain enzymes that break down various substances, including worn-out cell parts, foreign invaders, and cellular waste products.

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Cancer Therapy

The treatment of cancer using various methods like surgery, chemotherapy, radiation therapy, and immunotherapy.

Cancer therapy aims to eliminate or control the growth of cancerous cells. Different approaches target different aspects of cancer development and progression.

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LC3

Microtubule-associated protein 1A/1B-light chain 3

LC3 is a protein involved in autophagy. It's often used as a marker to study and monitor autophagic processes.

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Stapled Peptides

A type of modified peptide with a covalent bond linking specific amino acids, enhancing its stability and binding affinity.

Stapled peptides are engineered versions of naturally occurring peptides. The 'staple' is a chemical modification that improves their structure and makes them more effective at interacting with target proteins.

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Molecular Simulation

Computer-based modeling techniques used to simulate molecular interactions and predict their behavior.

Molecular simulations use computational power to mimic how molecules interact at the atomic level. This helps researchers understand how drugs bind to their targets and design more effective therapies.

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Free Energy Approaches

Computational methods used to calculate the energy changes associated with molecular interactions.

Free energy approaches help determine how stable a molecule is in a particular environment. This information is crucial for understanding drug binding and designing molecules with desired properties.