Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of PDE are referring to cyclic nucleotide phosphodiesterase. while, the superfamily of PDE enzymes is classified into 11 families, namely PDE1-PDE11 in mammals. Particularly, the PDE4 family of enzymes is the most prevalent PDE in immune cells. PDE4 is a cAMP-specific hydrolase present predominantly in host leukocytes, including macrophages, neutrophils and lymphocytes. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system. PDE4 inhibitors is a group of anti-inflammatory agents, which block the degradative action of PDE4 on cAMP.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is a common infectious disease.
The current anti-TB drug regimen used for directly observed therapy, short course (DOTS) is ineffective at completely eliminating the infecting Mtb and disease associated lung pathology. PDE4 inhibitors have been tested in different animal models as adjunctive therapy to anti-TB antibiotics, and the results suggest that this adjunctive therapy helps limit pulmonary damage.
Dovramilast (also known as CC-11050) is a potent and orally active phosphodiesterase 4 (PDE4) inhibitor. Dovramilast is an anti-inflammatory agent. So far, Dovramilast can decrease levels of multiple pro-inflammatory cytokines and chemokines. More importantly, Dovramilast is an adjunct to Isoniazid (INH) treatment in a mouse model of pulmonary Mycobacterium tuberculosis (Mtb) infection. For example, in the rabbit model of pulmonary tuberculosis (TB), Dovramilast plus Isoniazid significantly reduces bacillary load and pathology. In addition, Dovramilast inhibits the expression of host genes associated with tissue remodeling, TNF-α regulation, macrophage activation, and lung inflammation networks. In a mouse model of pulmonary Mtb infection, Dovramilast plus Isoniazid significantly improves Mtb control and pathology in the lungs of mice. Moreover, Dovramilast also has the potential for research of the lupus erythematosus and HIV-related inflammation.
To sum up, Dovramilast is a potent and orally active PDE4 inhibitor with an anti-inflammatory effect, and it has the potential for research of tuberculosis.