Editorial [Hot Topic: Emerging Therapeutic Opportunities by Targeting Protein-Protein Interactions (Guest Editor: Dr. Rosario Gonzalez-Muniz)]

During the last years, the explosion in genomics and proteomics has triggered the discovery of new targets for therapeutic intervention based on protein-protein interactions (PPIs). This emanate from the importance of protein associations and networks in a large number of cellular processes, including signal transduction, transcription, cellular trafficking, and mitosis, while the dysregulation of PPIs is in the origin of many pathological states. Protein-protein interconnections are also important inputs on the way to bacterial and viral infections. As a result, the search of modulators either of altered, inappropriate PPIs in human cells or of PPIs crucial to pathogen invasion, survival and replication is an issue of major interest in the field of new medicines. However, protein-protein interactions are clearly more challenging targets than enzymes and receptors that usually bind small molecules: a better understanding of protein complexes and their interconnections, and a deeper knowledge of the structure of protein interfaces and key points of intervention (hot-spots) are still need, and we have to press hard on the development of general strategies to modulate these interactions. This issue of Current Topics in Medicinal Chemistry, dedicated to “Emerging Therapeutic Opportunities by Targeting Protein-Protein Interactions”, is aimed at describing the state of the art of current research and development in the field. The first two reviews focus on the complexity of protein-protein networks and the opportunity of interfering within PPIs by means of peptide molecules. Kumlesh K. Dev provides a complete biochemical characterization of the interactions of the PDZ domain of PICK1 with a plethora of proteins, including among others the family of protein kinase receptors, ionotropic and metabotropic glutamate receptors, and different synaptic proteins and transporters. He then makes a brief description of peptides and small molecules able to block PDZ interactions, and highlight their interest as pharmacological tools to study the role of PICK1 in different pathological processes. Erika Nieddu and Stefania Pasa, using c-Myc as a case study, review the way to built and the usefulness of molecular interaction maps (MIMs) for the compilation of available PPI data, the formulation of hypotheses for experimental testing, and the identification of appropriate molecular targets for therapeutic intervention. They selected several examples to illustrate the potential of peptides as starting point to find out PPI inhibitors, and describe a retroinverse peptide analogue, developed as a disruptor of the c-Myc-INI1 interaction, active against proliferation in cancer cell lines. As in classical medicinal chemistry, the discovery of modulators of protein-protein interactions can follow different approaches according to the degree of knowledge about protein-protein interfaces. The review by Pérez de Vega et al. provides representative examples of rationally designed conformationally restricted peptides and peptidomimetics able to disturb PPIs of therapeutic relevance. The challenge in this case is the identification of essential secondary structural elements (hot-spots) of protein-protein interfaces, followed by the transformation of these protein fragments into mimetics of α-helices, β-sheets, and reverse turns. In the fourth review, Zhong, Macias and MacKerell make convincing arguments in favor of the use of computeraided drug design and virtual screening for identifying PPI inhibitors. After providing general principles of database screening and a basic protocol for targeting PPIs, they illustrate the usefulness of this alternative rational approach with recent examples from different laboratories. When information about protein complexes is not available, combinatorial chemistry is a valuable tool both for the discovery of PPI modulators and for the identification and subsequent validation of PPIs as potential therapeutic targets. In this context, Vicent et al. highlight the principles of combinatorial approaches and their suitability to target PPIs involved in apoptosis, cell cycle, cell migration, and viral replication, among others. Paige and Jaffrey provide an extensive examination of the progress in the development of isoform-specific NOS-directed therapeutics, from molecules that target the Arg-binding site to dimerization inhibitors. Moreover, they discuss about emerging approaches directed to stabilize NOS dimmers or to modulate the interaction of NOS isoforms with other proteins, which could be advantageous over dimerization inhibitors to control NO-related diseases. The contribution by Estrada and Soto begins by providing a clear description of Alzheimer's disease (AD) and the role of amyloid beta (Aβ) peptide as one of the causative agents of this neurodegenerative process......