Histone deacetylase (HDAC) inhibitors have shown partial efficacy toward correcting cystic fibrosis transmembrane conductance regulator (CFTR) protein function in ΔF508- CFTR models. While current treatment options for CF generally concentrate on disease symptoms such as management of inflammation and bacterial infection, therapy using HDAC inhibitors has the potential to treat and correct the underlying etiology associated with the disorder. Subsequently, we have synthesized conformationally well-defined cyclic tetrapeptide derivatives based on the natural product HDAC inhibitor Apicidin, in order to formulate a pharmacophore model to describe and enhance the bioactivity of these molecules. Through this study we have developed HDAC inhibitors which improve CFTR trafficking from the endoplasmic reticulum (ER) while ultimately increasing ion conductance across the plasma membrane of a lung epithelial cell line expressing ΔF508-CFTR.