Autoimmune diseases are chronic inflammatory diseases of unknown etiology that results from the combination of genetic susceptibility, environmental factors, and immune dysregulation. There are more than 80 human diseases currently classified as autoimmune, including multiple sclerosis, inflammatory bowel diseases, type 1 diabetes mellitus, rheumatoid arthritis, and systemic lupus erythematosus. Since they affect up to 8% of the US population and often attack young adults, especially women, their social and economic impact is enormous. Immunosuppressive drugs are classical therapies to treat a wide range of autoimmune diseases. However, the treatment of autoimmune diseases has been based on non-selective immunosuppressants or cytotoxic drugs that in general offer a limited clinical efficacy. Even more selective immunosuppressive drugs such as cyclosporine A and FK506 possess serious side effects, including acute neurological toxicity and chronic nephrotoxicity. Biologicals are expensive and some patients do not respond to them adequately. Thus, efforts must be made to identify new immunomodulatory agents that are effective through a novel mechanism to circumvent existing side effects and more selective to reduce off-target effects. Subglutinols A and B are ?-pyrone diterpenoid natural products with a novel chemical scaffold. They showed potent immunosuppressive activity comparable to that of cyclosporine A. We reported the first total synthesis of subglutinols A and B and demonstrated that they show multimodal immune-suppressive effects on activated T cells and possess a significant therapeutic window. We further revealed that subglutinols might exert their anti-inflammatory effects by affecting T cell metabolism which has been yet to be explored as an autoimmune disease target. All together, our data suggests that subglutinols A and B may have great potential for safe immunosuppressive therapeutics for autoimmune diseases with a novel and unique mode of action. The objective of this proposal is to identify the molecular target(s) of subglutinols to establish their mode of action and to develop subglutinol-derived chemical probes to study the regulation mechanism of immune responses through the following specific aims: (1) Identify the molecular target(s) and mode of action of sublutinols and (2) Determine the key pharmacophores of subglutinols. If successful, such therapeutics and drug targets are expected to be useful for the treatment of autoimmune diseases and for post-transplantation care, thus resulting in a sustained remission of the disease and better patient outcome.

Public Health Relevance

The number of options available to treat autoimmune diseases has increased over the past several decades. However, current therapies for autoimmune diseases possess serious side effects and autoimmune diseases still remain major health issues in the US as well as worldwide. Thus, there is an urgent medical need to develop immunomodulatory agents with novel mechanisms to circumvent existing side effects. Subglutinols A and B are novel immunosuppressive natural products with an as yet unknown mode of action that may be unique among other reported immunosuppressive agents. This proposal aims to identify the molecular target(s) of subglutinols and to establish their mode of action. If successful, it will eventually lead to novel, innovative approaches to the treatment of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI128283-02
Application #
9397515
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lapham, Cheryl K
Project Start
2016-12-09
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Lanier, Megan L; Park, Hyeri; Mukherjee, Paramita et al. (2017) Formal Synthesis of (+)-Laurencin by Gold(I)-Catalyzed Intramolecular Dehydrative Alkoxylation. Chemistry 23:7180-7184