Epigenetics and airways disease

Epigenetics is the term used to describe heritable changes in gene expression that are not coded in the DNA sequence itself but by post-translational modifications in DNA and histone proteins. These modifications include histone acetylation, methylation, ubiquitination, sumoylation and phosphorylation. Epigenetic regulation is not only critical for generating diversity of cell types during mammalian development, but it is also important for maintaining the stability and integrity of the expression profiles of different cell types. Until recently, the study of human disease has focused on genetic mechanisms rather than on non-coding events. However, it is becoming increasingly clear that disruption of epigenetic processes can lead to several major pathologies, including cancer, syndromes involving chromosomal instabilities, and mental retardation. Furthermore, the expression and activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in the airways of patients with respiratory disease. The development of new diagnostic tools might reveal other diseases that are caused by epigenetic alterations. These changes, despite being heritable and stably maintained, are also potentially reversible and there is scope for the development of 'epigenetic therapies' for disease

The first biologically active synthetic analogues of FK228, the depsipeptide histone deacetylase inhibitor

The FK228 and spiruchostatin bicyclic depsipeptide natural products are among the most potent histone deacetylase (HDAC) inhibitors known. Although FK228 is in advanced clinical trials, the complexity of the natural products has precluded mechanistic studies and the discovery of structure-activity relationships. By total synthesis, we have prepared the first depsipeptide analogues. Our results prove that the dehydrobutyrine residue in FK228 is not essential, and other residues can be substituted without loss of HDAC inhibitory activity. Conformational restriction by the macrocyclic scaffold is important, as a linear peptide was inactive. The intramolecular disulfide formed with a cysteine side chain can be removed provided the zinc-binding thiol is protected to ensure good cellular availability. Like the natural products, the analogues are selective against class I isoforms, with nanomolar inhibition of class I HDAC1 and significantly less potency against class II HDAC