University of Pittsburgh researchers have identified several compounds capable of increasing cellular nicotinamide adenine dinucleotide (NAD) levels. Aging is linked to lower NAD levels, impacting cellular energy metabolism and production, in turn contributing to age-related decline in muscle and neuronal function. The use of orally available small molecules could be a novel approach to treating a variety of age-related conditions.
Description
The global population is aging and comes with increasing prevalence of age-related conditions. These age-related conditions may require increased care needs, placing strain on both financial and health services. Given the decline in NAD levels as we age, developing new ways to increase intracellular NAD could be a novel strategy to tackling many of the diseases of aging, increasing health span and improving quality of life for an ageing population.
Applications
1. Aging 2. Degenerative disorders 3. Metabolic disorders
Advantages
Nicotinamide phosphoribosyl transferase (NAMPT) is a key enzyme in the production of NAD. Therefore, increasing NAMPT activity with small molecules could be an effective approach to increasing NAD levels. Using a discovery process consisting of high throughput screens to identify potential NAMPT binders, assessing the top hits and investigating structure activity relationships (SAR), several effective small molecules were identified as capable of increasing cellular NAD level. These compounds could be orally active and provide a novel approach to restore or augment NAD levels and potentially reverse or prevent age-dependent decline.
Invention Readiness
Using a high throughput screen 100,000 compounds were assessed for their ability to bind to NAMPT. The top 360 compounds were further tested in a cell-based NAD+. The top three hits were used to increase NAD+ levels in iPSC-derived neurons. A library of 1.6 million compounds was searched to find similar structures to these hits and a clear SAR was identified leading to the synthesis of >100 novel compounds. Further testing found compounds were not only metabolically stable but capable of increasing NAD+ levels by 25%, believed to be biologically meaningful at <500 nM doses. Of note, another compound was found to increase cellular NAD in a NAMPT-independent manner which could also prove to be a novel strategy to target diseases of aging. Three NAMPT-dependent and one NAMPT-independent compounds were found to efficiently increase cellular NAD levels in muscle myotube and NASH patient hepatocytes.
IP Status
https://patents.google.com/patent/US20230310424A1
