Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein–protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as “undruggable” targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.

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Objective-Atherosclerosis is a focal disease that occurs predominantly at branches and bends of the arterial tree.Endothelial cells (EC) at atherosusceptible sites are prone to injury, which can contribute to lesion formation, whereas EC at atheroprotected sites are resistant. The c-Jun N-terminal kinase (JNK) is activated constitutively in EC at atherosusceptible sites but is inactivated at atheroprotected sites by mitogen-activated protein kinase phosphatase-1 (MKP-1). Here, we examined the effects of JNK activation on EC physiology at atherosusceptible sites. Methods and Results-We identified transcriptional programs regulated by JNK by applying a specific pharmacological inhibitor to cultured EC and assessing the transcriptome using microarrays. This approach and subsequent validation by gene silencing revealed that JNK positively regulates the expression of numerous proapoptotic molecules. Analysis of aortae of wild-type, JNK1Ϫ/Ϫ, and MKP-1 Ϫ/Ϫ mice revealed that EC at an atherosusceptible site express proapoptotic proteins and are primed for apoptosis and proliferation in response to lipopolysaccharide through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of proapoptotic molecules and were protected from injury by MKP-1. Key Words: apoptosis Ⅲ arterial endothelium Ⅲ atherosusceptibility Ⅲ c-Jun N-terminal kinase Ⅲ mitogen-activated protein kinase phosphatase-1 A therosclerosis is characterized by the accumulation of cells, lipids, and extracellular matrix in the wall of an artery, which can result in occlusion of the vessel lumen. It develops predominantly at branches and bends that are exposed to disturbed patterns of blood flow, whereas regions exposed to uniform flow are protected. [1][2][3][4] The molecular mechanism underlying the distinct spatial distribution of lesions is likely to involve apoptosis. Regions that are predisposed to atherosclerosis are characterized by relatively high rates of endothelial cell (EC) injury and turnover, [5][6][7] and apoptosis can be induced in cultured EC by the application of atheroprone flow patterns. 8,9 A causal relationship between apoptosis and atherosclerosis was established by enforcing expression of a proapoptotic molecule in arterial EC, which enhanced the accessibility of lipoproteins and leukocytes to arteries and initiated lesion formation in hypercholesterolemic mice. 10 In addition, focal endothelial apoptosis/injury in atherosclerotic lesions can, in turn, lead to endothelial denudation and exposure of a procoagulant vascular wall, a major cause of coronary thrombosis. 11,12 Several proatherogenic agents are known to induce EC apoptosis, including oxidized low-density lipoproteins, 13 reactive oxygen intermediaries (eg, H 2 O 2 14 ) and proinflammatory mediators (eg, lipopolysaccharide [LPS], 15 tumor necrosis factor [TNF]-␣ 16 ) by activating distinct signaling pathways that converge to cleave procaspase-3 into the active form of caspase-3. Cleaved caspase-3, in turn, executes apoptosis by activating numerous downs...