Therapeutic Approaches Interfering with Nuclear Localization Signals: An Emerging Strategy for CNS-Related Diseases

Although medicinal chemistry is constantly looking for new therapeutic approaches against pathological conditions affecting the central nervous system (CNS), such as neurodegeneration and cancer, this quest has not been fully successful yet. The lack of understanding of all the complex mechanisms underlying these conditions makes the identification of new effective drugs challenging. A wide variety of pathophysiological events are regulated at both nuclear and cytoplasmic levels, and in this context, targeting the shuttle system composed of the karyopherin superfamily and their cargoes may provide an alternative strategy. Molecular recognition is highly specific and strictly related to the presence of special “tag” regions, known as nuclear localization signals, that are localized in the amino acid sequences of cargoes. Importantly, their trafficking is involved in various pathophysiological processes, including CNS diseases. Curiously, although this system has been studied intensively, much remains to be discovered to date. Throughout the years, drug discovery allowed the identification of small molecules and peptides able to target karyopherin-cargo complexes to provide new potential pharmacological treatments. Indeed, the first examples of drug candidates targeting this mechanism that reached clinical trials are appearing in the literature. With this mini-review, this study aims at presenting an updated overview on the most recent reports investigating the use of the karyopherin shuttle system as a new therapeutic target especially for CNS-related diseases.