RESEARCH: CANCER
FOLDING PROJECT #18429 PROFILE

This project studies how small proteins called peptides can block autophagy, a process that cleans up cells. The goal is to design better peptides that can be used as cancer treatments. Scientists use computer models to understand how these peptides work and how to improve 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 that plays a role in autophagy, the process of cellular recycling. It's also a target for cancer therapies.

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Autophagy

The process of cellular recycling.

Autophagy is a natural process where cells break down and recycle their own components. This helps to remove damaged parts and provides energy for the cell.

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Lysosomes

Organelles within cells that break down waste materials.

Lysosomes are like the recycling centers of cells. They contain enzymes that break down waste products and cellular debris.

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Cancer Therapy

Treatment for cancer.

Cancer therapy aims to treat and control the growth of cancerous cells. This can involve surgery, chemotherapy, radiation therapy, or immunotherapy.

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Stapled Peptide

A type of peptide with a chemical modification that increases its stability.

Stapled peptides are designed to be more stable and effective than regular peptides. They're used in drug development to target specific proteins.

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Molecular Simulation

Computational method to predict the behavior of molecules.

Molecular simulation uses computer models to simulate the interactions between atoms and molecules. This helps researchers understand how drugs work and design new ones.

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Free Energy

A measure of the energy available to do work.

Free energy is a fundamental concept in chemistry that describes the amount of energy available for a chemical reaction to occur. It helps predict whether a reaction will be spontaneous.

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N-methylation

A chemical modification that adds a methyl group to an amine group.

N-methylation is a common way to modify peptides and proteins. It can alter their properties and make them more effective as drugs.

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Peptide

A short chain of amino acids.

Peptides are small proteins that play many important roles in the body. They can act as hormones, enzymes, and signaling molecules.