► More than 100 CPPs are presented, divided into cationic, amphipathic, and hydrophobic. ► Origin-based classification: natural proteins/peptides; designed; random libraries ► Natural sources of ...CPPs: heparin-, DNA/RNA binding proteins; viral proteins; antimicrobial/signal peptides.
With more than ten new FDA approvals since 2001, peptides are emerging as an important therapeutic alternative to small molecules. However, unlike small molecules, peptides on the market today are limited to extracellular targets. By contrast, cell-penetrating peptides (CPPs) can target intracellular proteins and also carry other cargoes (e.g. other peptides, small molecules or proteins) into the cell, thus offering great potential as future therapeutics. In this review I present a classification scheme for CPPs based on their physical–chemical properties and origin, and I provide a general framework for understanding and discovering new CPPs.
CPPs differ from most other peptides with respect to specific features that reflect various mechanisms used to enter the cell.
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•The main organoselenium species have different structural properties.•We focus on selenium containing heterocycles and natural products.•We provide information to guide the rational ...design of selenium-containing drugs.
The diverse pharmacological activities of organoselenium compounds are closely correlated to their ability to scavenge and induce reactive oxygen species (ROS), their intrinsic oxidative properties, and their Se(0) release property. The incorporation of selenium into small molecules, and particularly into heterocycles and natural products, has shown great potential in altering the potency and selectivity of these molecules. Therefore, selenium will play an important role in drug discovery in the near future. We summarize how different organoselenium species affect cellular oxidative stress levels, and try to correlate the structural properties of selenium-containing heterocycles and natural product derivatives to their biological activities and therapeutic applications. We also provide some information to guide the rational design of selenium-containing drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•High quality building blocks can have a big impact on drug discovery.•Commercial reagents do not satisfy our design criteria or provide sufficient SAR.•Design principles for design of novel building ...blocks are outlined.•Analysing reagent usage is a useful approach to improving our design.•Future perspective: open innovation or collection sharing between companies.
One pragmatic way to improve compound quality, while enhancing and accelerating drug discovery projects, is the ability to access a high quality, novel, diverse building block collection. Here, we outline general principles that should be applied to ensure that a building block collection has the greatest impact on drug discovery projects, by discussing design principles for novel reagents and what types of reagents are popular with medicinal chemists in general. We initiated a program in 2009 to address this, which has already delivered three candidate drugs, and the success of that program provides evidence that focussing on building block design is a useful strategy for drug discovery.
The rational design of novel, high quality building blocks can accelerate drug discovery projects and improve compound quality, but has been overlooked in the medicinal chemistry literature.
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•The development of efficacious ocular drug delivery systems to treat diseases of the back of the eye faces many challenges due to the unique anatomy and physiology of the eye.•Nanotechnology in ...ophthalmic formulations may improve the therapeutic efficacy of some drug therapies.•The development of minimally or noninvasive drug delivery systems shows positive preclinical outcomes in animal models.•For the successful clinical translation of any ocular drug delivery technology, the use of appropriate animal models is key.
Drug delivery to the posterior segment of the eye remains challenging even though the eye is readily accessible. Its unique and complex anatomy and physiology contribute to the limited options for drug delivery via non-invasive topical treatment, which is the prevalent ophthalmic treatment. To treat the most common retinal diseases, intravitreal (IVT) injection has been a common and effective therapy. With the advancement of nanotechnologies, novel formulations and drug delivery systems are being developed to treat posterior segment diseases. Here, we discuss the recent advancement in ocular delivery systems, including-sustained release formulations, IVT implants, and preclinical topical formulations, and the challenges faced in their clinical translation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Role of ER stress and autophagy in the pathogenesis of diabetes.•ER stress and autophagy crucial in diabetic microvascular complications pathogenesis.•Modulation of ER stress and autophagy as novel ...strategy against diabetic complications.•ER stress and autophagy interplay in diabetic microvascular complications.
Endoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS.
Endoplasmic reticulum stress, autophagy, and their interplay are crucial in the development of diabetes and associated microvascular complications, requiring further investigations.
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Detection, comparison and analyses of binding pockets are pivotal to structure-based drug design endeavors, from hit identification, screening of exosites and de-orphanization of protein functions to ...the anticipation of specific and non-specific binding to off- and anti-targets. Here, we analyze protein–ligand complexes and discuss methods that assist binding site identification, prediction of druggability and binding site comparison. The full potential of pockets is yet to be harnessed, and we envision that better understanding of the pocket space will have far-reaching implications in the field of drug discovery, such as the design of pocket-specific compound libraries and scoring functions.
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•Rabs are dysregulated in human cancers.•Rabs regulate cell signaling pathways in cancer.•Rabs regulate the secretory pathway in cancer.•Rabs are novel therapeutic targets.
Rab GTPases constitute the ...largest family of small GTPases. Rabs regulate not only membrane trafficking but also cell signaling, growth and survival, and development. Increasingly, Rabs and their effectors are shown to be overexpressed or subject to loss-of-function mutations in a variety of disease settings, including cancer progression. This review provides an overview of dysregulated Rab proteins in cancer, and highlights the signaling and secretory pathways in which they operate, with the aim of identifying potential avenues for therapeutic intervention. Recent progress and perspectives for direct and/or indirect targeting of Rabs are also summarized.
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Several cytokines have been investigated in clinical trials, based on their potent therapeutic activity observed in animal models of cancer and other diseases. However, substantial toxicities are ...often reported at low doses, thus preventing escalation to therapeutically active regimens. The use of recombinant antibodies or antibody fragments as delivery vehicles promises to enhance greatly the therapeutic index of pro-inflammatory and anti-inflammatory cytokines. This review surveys preclinical and clinical data published in the field of antibody-cytokine fusions (immunocytokines). Molecular determinants (such as molecular format, valence, target antigen), which crucially contribute to immunocytokine performance in vivo, are discussed in the article, as well as recent trends for the combined use of this novel class of biopharmaceuticals with other therapeutic agents.
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•Split biosensor assays allow monitoring of dynamic protein–protein interactions in cell-based assays.•The activity of druggable targets, such as GPCRs and RTKs, can be sensitively and robustly ...assessed.•Readouts include bioluminescence, fluorescence and adaptable transcriptional reporters.•Split biosensor assays are amenable to cell-based high-throughput formats and animal models.•Transcription-based molecular barcoding techniques enable applications in multiplexed cell-based assays.
Cellular signalling is commonly mediated through dynamic protein–protein interactions (PPIs). When pivotal PPIs are deregulated, cellular signalling can be altered; it is therefore attractive to monitor regulated PPIs to understand their role in health and disease. Genetically encoded biosensors that rely on protein fragment complementation have made it feasible to monitor PPIs in living cells precisely and robustly. In particular, split protein biosensors using fluorescent proteins or luciferases are frequently applied. Further, split TEV and split ubiquitin biosensor platforms flexibly allow using readouts of choice, including transcriptional barcode reporters that are amenable to multiplexed high-throughput formats and next-generation sequencing. Combining these technologies will enable assessing drug target activities and cellular response profiles in parallel, thereby opening up new avenues in drug discovery.
Genetically encoded split biosensors based on protein fragment complementation are a sensitive and robust tool for monitoring dynamic protein–protein interactions and activities of druggable targets in cell-based assays.
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•Triterpenoids work as reversal agents for anticancer drug resistance treatment.•The chemical and anticancer properties of triterpenoids are introduced here.•The findings and mechanisms of ...triterpenoids reversing multidrug resistance (MDR) are summarized.•Triterpenoids might be the potential chemosensitizers for anticancer treatment.
Overexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR), which is one of the major obstacles in the treatment of cancer patients. None of the strategies to overcome MDR has been successfully applied in the clinic until now. Plenty of evidence shows that some triterpenoids function as reversal agents of MDR for anticancer drug resistance treatment. Here, we review the latest findings of reversing cancer MDR with triterpenoids. Findings are summarized showing that triterpenoids are MDR modulators and potential chemosensitizers. Finally, we contemplate future prospects of modulating MDR in the clinic.
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