Novel Molecules to Tackle Toxic Amyloid-Beta Production in Alzheimer's

The project aim is to generate potential drug candidates by determining how small regulatory molecules interact with an important Alzheimer’s protein and designing similar molecules.

An enzyme called gamma-secretase has important biological functions. When it is not properly regulated, though, it can boost production of a toxic form of the Alzheimer’s disease protein amyloid-beta. Under proper regulation, the very same enzyme can promote processing of nontoxic amyloid-beta while still executing its normal functions.

Lucía Chávez-Gutiérrez, PhD, and her team aim to examine the molecules responsible for regulating the activity of gamma-secretase. They first will capture how these molecules interact with the enzyme. Using these interactions as a template, they will design novel molecules with similar features and predicted behaviors.

With these designed molecules in hand, Dr. Chávez-Gutiérrez and her group will use molecular biology tools to assess how well the novel molecules boost production of nontoxic amyloid-beta without inhibiting the important normal functions of gamma-secretase. The work, which is the first to apply this rational, genetic-based approach to drug design in this context, is predicted to generate new candidates for drug development.

For the first time, we will apply a rational, genetic-based approach to the design of effective and safe drugs that modulate beta-amyloid generation to address toxic amyloid production in the brain.

A solid molecular understanding of the pharmacological modulation of amyloid-beta production by small compounds (gamma-secretase modulators, GSMs) and novel molecules for the potential development of next-generation GSMs.