Longevity
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Summary
Our bodies are equipped with various pathways that help manage stress at a cellular level. However, when these pathways are overactivated, they can lead to diseases. We’re interested in a specific pathway known as p38α-TAB1. You can think of it as a central road network in a city, crucial for managing traffic - proper flow keeps the city healthy, and traffic jams cause chaos. One such example of ‘chaos’ in our bodies leads to a condition called retinopathy, where the retina gets damaged. Currently, there are 196 million people in the world who suffer from age-related vision impairment, often leading to blindness.
Led by Dr Gian de Nicola, a structural biologist from Kings College London, we uncovered the structural changes in the protein which tells us where and how drugs can attach. We then developed a novel technique combining X-ray crystallography and fragment screening, where small chemical fragments are tested for binding to the relevant protein.
Our next step is to create small molecules that are able to modify the p38α-TAB1 pathway, a project supported by the $175,350 we hope to raise on Catalyst. The anticipated outcome is a new, non-invasive treatment for age-related vision loss, offering a significant improvement over the current standard of care - an injection directly into the eyeball.
Problem
Aging was found to increase the prevalence of any type of retinopathies. WHO estimated that the number of people affected by age-related macular degeneration (AMD) is 196 million, while diabetic retinopathy (DR) is 146 million, worldwide in 2020. Our research aims to develop small molecule inhibitors that can act like "smart traffic lights" to reduce excessive pathway activity selectively. This targeted approach can prevent retinal damage and vision loss without disrupting the pathway's essential functions elsewhere, offering a new and effective treatment for retinopathy and potentially other diseases involving stress pathway dysregulationSolution
In our quest to combat retinopathy, we have focused on a so far less-explored route in cellular signaling, the "non-canonical" activation of the key cellular signaling mediator p38α via TAB1. Our innovative approach targets this specific pathway with precision, bypassing the mechanistical cause for disappointing results of clinical studies in the past, which often show off-target effects and toxicity. By employing small molecule inhibitors, we aim to act like smart traffic management systems at a cellular level, directly mitigating disease activity at its source. This targeted intervention promises to alleviate retinopathies without the side effects that plague current therapies. By sparing the rest of the body's cellular "traffic" from unnecessary disruption, our approach offers a safer, more effective treatment avenue, paving the way for a future where vision loss can be prevented with minimal risk.
Commercialization potential
Our pioneering research on selective inhibition of p38α signaling through disrupting its interaction with TAB1 presents a unique opportunity as it addresses a not yet targeted non-canonical pathway of p38α activation that does not interfere with its usual physiological activity profile. Small molecule inhibitors we developed for retinopathies are poised to generate significant novel intellectual property (IP) with first-in-class potential for various indications. Thus, we feel confident that we will be able to attract follow-up financing to achieve full pre-clinical derisking after completing the hereby proposed initial hit discovery.
Intellectual Property
The uniqueness of selectively targeting the p38α-TAB1 interaction offers substantial opportunities for IP generation. We intend to file patents covering the novel small molecules, their method of use in treating specific diseases, and any novel delivery mechanisms discovered. Securing robust IP protection will serve as necessary basis for attracting venture capital investment and pharmaceutical partnerships necessary for advancing our identified drug candidates into clinical trials and potential market approval.
Use of funding
With $243,600 USD of funding, we will leverage advanced AI-driven analysis to develop a novel compound library targeting p38⍺ and TAB1 proteins, aiming to enhance precision and efficacy in respective disease treatments. Our working approach integrates computation, synthesis, and experimental assays to pioneer the discovery of novel small molecules for improved therapeutic outcomes. The total duration of the project spans 12 months.
Specific Allocations:
| Item | Description | Timeline and Cost |
|---|---|---|
| Milestone 1: Protein-ligand binding free energy calculations | Perform computer-based screenings and analyses to find potential inhibitors with better binding abilities. | 3 months, $25,000 |
| Milestone 2: Ligand synthesis and optimization | Synthesize around 10-15 ligands based on computational screening results. Optimize the synthesis process to ensure high purity and adequate quantities of ligands. | 6 months, $25,000 |
| Milestone 3: In vitro binding affinity and efficacy assays | Synthesize and purify p38α and TAB1 proteins. Measure binding affinity using isothermal titration calorimetry (ITC). Assess ligand efficacy with in vitro kinase assay (IVKA). | 3 months, $95,000 |
| Consumables | Materials required for experiments | $22,000 |
| Salaries and University overheads | Standard costs associated with sponsoring research at a university, including researcher salaries and administrative costs. | $65,000 |
| Liquidity Pool | 5% of the funding amount will go toward project liquidity | $11,600 |
| Total | - | $243,600 |
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