Improving healthspan through discovery of potent NAMPT activators from a DNA-encoded library

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Abstract Advancing age is a primary risk factor for numerous chronic diseases including cardiovascular and metabolic diseases, as well as sarcopenia. Increasing evidence suggests that the levels of the cofactor NAD+ and the activity of NAD+-dependent proteins such as sirtuins have close links to the process of aging and development of chronic diseases. While many studies exploring the health benefit of nutritional supplementation with sirtuin activators and NAD+-precursors have had encouraging preclinical results, there are currently no drug candidates that directly act on NAD+-metabolism. The objective of the proposed research project is to develop a potent activator of nicotinamide phosphorybosyltransferase (NAMPT), the enzyme that catalyzes the rate limiting step in NAD+ synthesis, and to evaluate its ability to reverse age-related physiological dysfunction in a preclinical mouse model. Although previous studies have established that NAMPT activation can have age- delaying and disease-preventing effects, no currently available therapeutics are directed at modulating NAMPT activity per se. The proposed research addresses the key limitation towards accessing such drug candidates, which is the lack of a potent, selective, and mechanistically validated lead molecules for NAMPT activation with a favorable absorption, distribution, metabolism and excretion (ADME) profile. To access such a compound, in the R21 phase of this application, we propose to develop and screen a NAMPT-focused DNA-encoded chemical library and to use computational drug discovery methods to advance screening hits into potent lead candidate compounds. The efficacy of NAMPT activators will be tested with in vitro assays and in three different cell lines. Once candidate compounds are identified, the R33 phase will consist, first of comprehensive pharmacokinetic studies in lead candidate compounds to determine the appropriate dose and route of administration for in vivo studies. The lead compound will then be utilized to assess the impact of treatment on physiological measures of healthspan in middle-aged and old mice. The project, if successful, will deliver preclinical lead compounds for the development of first-in-class therapeutics that directly target the aging-related pathways of a wide range of chronic diseases. In the long term, such drugs may help decrease the morbidity and mortality of geriatric patients.