oa Editorial [Hot topic: The Protein-Protein Interactions as a Target in Medicinal Chemistry and Drug Discovery (Guest Editor: Gabriela Mustata)]

Protein-protein interactions are involved in the vast majority of biological processes that occur in living organisms from embryogenesis, cell-cell communication, receptor-ligand interactions, signal transduction pathways, gene transcription, metabolism, homeostasis and proliferation. Despite the potential importance of protein-protein interactions, researchers believed that finding small-molecule drugs to modulate PPIs would be nearly impossible, as protein-protein interfaces are generally large and devoid of well-defined cavities that can accommodate a small molecule, like those typically found on enzymes. Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This issue of Current Topics in Medicinal Chemistry, dedicated to “The Protein- Protein Interactions as a Target in Medicinal Chemistry and Drug Discovery”, is aimed at describing the state of the art of current research and development in the field. The first review by Meireles and Mustata provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. The authors selected several examples of successful discovery of modulators of protein-protein interactions for each of these strategies. The cellular machineries that are involved in biological processes are complex assemblies of protein-protein and proteinoligonucleotide interactions. Any disruption of this interaction can lead to disease, including cancer. Garner and Janda examine the progress in the field of protein-protein interactions in cancer, their main focus being on small molecules, non-peptidic inhibitors at the transcription, mRNA splicing and transcription level. Understanding the molecular mechanisms of regulating apoptosis, or programmed cell death, is one of the hottest research areas in biomedical sciences. Apoptosis plays a major role in normal organism development, tissue homeostasis, and removal of damaged cells. Decreased or inhibited apoptosis is a hallmark of many malignancies and represents a major causative factor in the development and progression of cancer. Among others, the interaction of PUMA (p53 upregulated modulator of apoptosis)/Bcl-2 like proteins is a critical regulatory step in apoptosis initiation, particularly important in initiating radiationinduced apoptosis and damage in the gastrointestinal and hematopoietic systems. The research article contributed by investigators from the University of Pittsburgh (Mustata et al.) demonstrate that the synergism created by combining computational with experimental was key to the identification of small-molecule PUMA inhibitors for mitigating radiation induced cell death. Defective apoptosis can also be interrupted by a family of proteins termed inhibitors of apoptosis (IAP), which block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. The contribution by Straub provides an extensive examination of the progress in the development of IAPs, the chemical matter of the inhibitors and the biology emerging from the research in this field. Ballatore and colleagues highlight both progress and challenges associated with the use of MT-stabilizing agents and small molecule inhibitors of tau aggregation as potential treatments of Alzheimer's disease (AD) and related neurodegenerative diseases, collectively known as tauopathies. In the first part of the review, the authors summarize the current understanding of tau-mediated neurodegeneration as well as the rationale for therapeutic intervention based on MT-stabilizing agents and inhibitors of tau aggregation. Different classes of MT-stabilizing agents are reviewed with a particular emphasis on their potential to be developed as novel treatments for central nervous system (CNS) diseases like AD and related tauopathies. Finally, the authors discuss the “state-of-the-art” in the area of small molecule inhibitors of tau aggregation. Protein-protein interactions are clearly more challenging than other drug targets. Nevertheless, despite their challenging nature, significant progress has been made by researchers to discover modulators of protein-protein interactions. Notwithstanding the numerous examples included herein, this special issue is by no means comprehensive in its coverage. The significant progress that has been made by researchers demonstrates clearly that this target class holds considerable potential for new therapies and that the field will further develop in the coming years. We hope that you will find this special issue interesting and stimulating enough to bring your research endeavors in the area of protein-protein interactions to a higher level.