Preface

Proteins are the executors of most cellular functions. The diversity of functional protein variants in a cell is astonishingly high, given that there are at most twenty thousand genes in the human genome. This diversity is a result of alternative splicing of mRNA, chemical modifications of proteins, and even protein conformational plasticity. Proteins and protein variants rarely function in an isolated state. They interact with each other and form multi-protein complexes to carry out their functions. It has been estimated that there are more than 100 000 protein–protein interactions in the human body. These interactions are highly dynamic, ranging from transient to stable interactions for performing intricate biological functions. In a highly regulated manner, protein–protein interactions play pivotal roles in diverse physiological processes.

Dysregulated protein–protein interactions have been found in a wide range of human diseases, presenting opportunities for therapeutic targeting. For example, the abnormal aggregation of neuronal proteins has been associated with the pathogenesis of many neurodegenerative diseases, like Huntington's Disease and Alzheimer's Disease. The emerging role of protein–protein interactions in the regulation of immune checkpoint mechanisms has attracted tremendous attention in oncology research and clinical translation. The interaction of PD-1 with PD-L1 serves as an effective target for the development of immune checkpoint inhibitors that disrupt their interaction. These PD-1/PD-L1 disruptors have revolutionized the way that we treat certain types of cancer, resulting in wide-spread efforts to discover small molecule inhibitors. Although enzymes and other classes of druggable targets remain the primary focus of the drug discovery and development efforts – for example, inhibition of protein kinases – protein–protein interaction interfaces have emerged as an entirely novel class of drug targets. The initial expectation was that it would be difficult to find small molecules that would disrupt protein–protein interactions. However, it turned out that it is possible to design or discover small molecules that can disrupt protein–protein interactions. The approval of Venetoclax as a Bcl-2 inhibitor by the US FDA for cancer treatment strongly supports this notion. Also, peptides form a useful class of molecules that can be developed as protein–protein interaction inhibitors.

In this monograph, we have attempted to compile several articles with a focus on developing protein–protein interaction inhibitors to keep readers abreast of the latest developments in this exciting area of drug discovery. To provide a molecular basis for this topic, the first article by Schreiber describes the characteristics of protein–protein interfaces. He explains the thermodynamic principles of protein–protein complex formation and structural changes associated with the complex formation. In the following chapter, Dunn et al. delineate aspects of human disease-related protein–protein interaction networks. They summarize many methods employed to generate protein–protein interaction networks. A significant section in that chapter describes the roles of PPI network analysis in different human diseases.

The discovery of protein–protein interaction inhibitors is now an important component of drug discovery programs. The article by Doyle et al. deals primarily with different methodologies that have been developed for high throughput screening for these inhibitors. That article also discusses several extant validation techniques once the lead compound is identified from the high throughput screens. In the same vein, Yang and Ivanov discuss computational modeling approaches used for guiding and reinforcing experimental methodologies for inhibitor design.

Protein–protein interfaces often have substantially different properties from enzyme active sites or substrate binding sites. This makes the design of small molecules challenging. Short peptides and peptidomimetics have now emerged as a new class of protein–protein interaction regulators. Many protein–protein interactions utilize an α-helix for interaction with its partner protein. Thus, short stabilized α-helices have emerged as lead inhibitory molecules. Yoo and Arora present the hydrogen bond surrogate method of generating a stabilized α-helix and its use as an inhibitor of several protein–protein interactions. Naiya et al. focus on three different aspects of the development of stabilized α-helical peptides as protein–protein interaction inhibitors: different methods of stabilization, pharmacokinetics and delivery methods, and clinical pipelines of these types of molecules.

The rest of the chapters in this monograph focus on case studies of designed and developed protein–protein interaction inhibitors in different disease areas. Watanabe and Osada described inhibitors of F-Box proteins, which are important in neoplastic diseases. They discuss both natural and synthetic compounds that inhibit these related proteins. Kump and Nikolovska-Coleska present recent progress towards developing inhibitors of Mcl-1, a Bcl-2 protein family member. Their primary focus is to survey clinical developments of several of these molecules. The primary focus of the chapter authored by Olp et al. is the bromodomain. Bromodomains recognize acetylated lysine residues of proteins and are important components of gene regulatory systems in eukaryotes. They have attracted attention as drug targets. Olp et al. discuss the state-of-the-art in this area, including protein-selective inhibitors, pan-BET inhibitors, and their potential clinical applications. Iralde-Lorente et al. discussed the targeting of 14-3-3 proteins. 14-3-3 proteins are an important group of adaptor proteins involved in interactions with a large number of protein partners. They play crucial roles in many disease areas, including neurodegenerative diseases and cancer. They discuss both the inhibitors and stabilizers of interactions with 14-3-3 proteins and their protein partners.

MDM2–p53 interaction has been a cornerstone of protein–protein interaction inhibitor development. This field saw the development of many generations of inhibitors, which did not advance through the clinical pipeline. Rew and Eksterowicz discuss the two most recent inhibitors in this field. cMYC is a transcription factor that is pivotal in many tumor types. Its dimerization partner is MAX. Fletcher and Prochownik focus on inhibitors of MYC–MAX dimerization. These classes of inhibitors may become an important lead for different types of cancers. Toll-like receptors (TLR) are important components of the innate immune response. Talukdar et al. report the development of small molecule modulators of TLRs that are localized in endo-lysosomal membranes, such as TLR-9. They outline the use of many TLR-agonists as vaccine adjuvants and TLR-antagonists as leads against auto-immune diseases.

This monograph introduces readers to important methodologies, as well as many new developments in the area of protein–protein interaction regulators. We hope this will be useful to scientists working in this field and may excite students to explore this area further for the development of the next generation of protein–protein interaction inhibitors.

Siddhartha Roy

Haian Fu