Transfidelity for Protein Stability

Neurodegenerative diseases such as Alzheimer's Disease are devastating conditions that impact millions globally. These diseases are driven by the misfolding and aggregation of proteins, which lead to brain cell death and cognitive decline. To make matters worse, as we age our cells become more error-prone, resulting in more errors during protein printing, causing proteins to clump together and form aggregates.

Project Transfidelity aims to solve this by improving the accuracy of protein printing, preventing toxic aggregates from forming. Led by Dr. Dimitri Scherbakov and Dr. Rashid Akbergenov, with over 50 years of combined experience in the lab, we have identified two molecules that may improve the efficiency of protein production, potentially preventing protein aggregates, hypothesized to cause dementia.

Despite the significant research funding allocated to neurodegenerative diseases, current therapies continue to treat the symptoms caused by the protein aggregates, with little progress made to stop or reverse disease. We’re trying to go after a potential root cause - rather than trying to clear aggregates once they are there, we aim to prevent them from forming in the first place by reducing the production of faulty proteins. With a clear path towards developing novel intellectual property (IP) and an ever-growing target market, we believe we are poised to make an impact on neurodegenerative disorders and the way we age.

Did you know that Alzheimer’s Disease (AD) begins decades before the first symptom appears? While we carry on with our daily lives, faulty proteins start to clump (aggregate) and gather in the brain, gradually building over time.

At a cellular level, you can imagine our cells as bustling factories, with ribosomes acting as protein printers. Ribosomes execute translation, printing and assembling proteins which are the essential workers that keep our bodies functioning. Translational fidelity is a measure of the accuracy of translation - as we age, translational fidelity goes down. This is what we want to change.

Project Transfidelity aims to take a new approach to treating neurodegenerative diseases by developing novel compounds that improve the accuracy of protein translation. In simple terms, we’re going to upgrade the factory’s quality control systems.

Prior to seeking funding from the DeSci community, we screened 2400 unique molecules in two different systems: cell-free and cell-based.

• Our cell-based systems allowed us to assess whether the molecules improve translational fidelity in cells.
• Our cell-free system allowed us to assess whether the molecules directly interacted with proteins involved in translation (translational machinery).

After performing these two experiments, we found five compounds (hits) that improve translational fidelity. Of those five, two improved translational fidelity without slowing down the speed of translation, which is critical to maintaining cell health. To our surprise, neither of the two compounds acted directly on translational machinery, indicating that these compounds may target another biological pathway that enables them to improve translational fidelity.

Here’s how we intend to move forward:

• We will verify our hits’ ability to reduce protein aggregation.
• We will also perform experiments that allow us to understand which pathway these compounds target (their mechanism of action).
• We will then pursue a ‘hit-to-lead’ campaign, where we will modify the hits to ensure they are best suited to become therapeutics. Here, we will seek to create and patent the compounds we find.
• The top compound will go through standard preclinical and clinical trials.

There is a high unmet need for effective treatments for neurodegenerative diseases and the growing prevalence of these conditions. Alzheimer's disease alone affects approximately 55 million people worldwide, with annual healthcare costs reaching $1.3 trillion. The final product of this research will be a small molecule to treat age-related disorders that would benefit from enhanced translation fidelity.

Patent Strategy

The project plans to:

• File patents for the novel compounds identified through screening, ensuring exclusive rights to the therapeutics developed.
• Additionally, patents could be sought for our innovative in vitro (mouse model) translation fidelity measuring system and the in vivo (cell model) screening system, which can be licensed to other companies for large-scale screening purposes.

The total project plan is $254,668 USD and our team needs your help! As some of the milestones will be performed in parallel, the total duration of the project spans 12 months.

For the full funding application navigate to project documents.