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Pathogenic antibiotic resistant bacteria pose one of the most important health challenges of the 21st century. The overuse and abuse of antibiotics coupled with the natural evolutionary processes of bacteria has led to this crisis. Only incremental advances in antibiotic development have occurred over the last 30 years. Novel classes of molecules, such as engineered antibodies, antibiotic enhancers, siderophore conjugates, engineered phages, photo-switchable antibiotics, and genome editing facilitated by the CRISPR/Cas system, are providing new avenues to facilitate the development of antimicrobial therapies. The informatics revolution is transforming research and development efforts to discover novel antibiotics. The explosion of nanotechnology and micro-engineering is driving the invention of antimicrobial materials, enabling the cultivation of "uncultivable" microbes and creating specific and rapid diagnostic technologies. Finally, a revival in the ecological aspects of microbial disease management, the growth of prebiotics, and integrated management based on the "One Health" model, provide additional avenues to manage this health crisis. These, and future scientific and technological developments, must be coupled and aligned with sound policy and public awareness to address the risks posed by rising antibiotic resistance.

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Peptide therapeutics has made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, highresolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with selected examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered 'undruggable'.

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Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents.

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Sulforaphane is a small molecule isothiocyanate which exhibits anticancer potential, yet its biological targets remain poorly understood. Here we employ a competition-based chemical proteomics strategy to profile sulforaphane's targets and identify over 500 targets along with their relative affinities. These targets provide a new set of mediators for sulforaphane's bioactivity, and aid understanding of its complex mode of action.

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Cyclic peptides, owing to their good stability, high resistance to exo- and to some extent endo-peptidases, enhanced binding affinity and selectivity towards target biomolecules, are actively investigated as biochemical tools and therapeutic agents. In this review, we discuss various commonly utilized synthetic strategies for cyclic peptides and peptoids (peptidomimetics), their important screening methods to identify the bioactive cyclic peptides and peptoids such as combinatorial beadbased peptide library, phage display, mRNA display etc. and recent advances in their applications as bioactive compounds. Lastly, we also make a summary and provide an outlook of the research area.

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Polyhistidine peptides are effective ligands to coat quantum dots (QDs). It is known that both the number of histidine (His) residues repeats and their structural arrangements in a peptide ligand play important roles in the assembly of the peptide onto CdSe/ZnS QDs. However, due to steric hindrance, a peptide sequence with more than six His residue tandem repeats would hardly coordinate well with Zn(2+) in the QD shell to further enhance the binding affinity. To solve this problem, a His-containing peptide ligand, ATTO 590-E2 G (NH)6 (ATTO-NH), was specifically designed and synthesized for assembly with QDs. With sequential injection of QDs and ATTO-NH into the capillary electrophoresis with fluorescence detection, strong Förster resonance energy transfer phenomenon between the QDs and the ATTO 590 dye was observed, indicating efficient self-assembly of the novel peptide onto the QDs to form ATTO-NH capped QDs inside the capillary. The binding stability of the ligand onto the QD was then systematically investigated by titrating with imidazole, His, and a his-tag containing competitive peptide. It is believed that this new in-capillary assay significantly reduced the sample consumption and the analysis time. By functionalizing QDs with certain metal cation-specific group fused peptide ligand, the QD-based probes could be even extended to the online detection of metal cations for monitoring environment in the future.

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Natural and traditional medicines, being a great source of drugs and drug leads, have regained wide interests due to the limited success of high-throughput screening of compound libraries in the past few decades and the recent technology advancement. Many drugs/bioactive compounds exert their functions through interaction with their protein targets, with more and more drugs showing their ability to target multiple proteins, thus target identification has an important role in drug discovery and biomedical research fields. Identifying drug targets not only furthers the understanding of the mechanism of action (MOA) of a drug but also reveals its potential therapeutic applications and adverse side effects. Chemical proteomics makes use of affinity chromatography approaches coupled with mass spectrometry to systematically identify small molecule-protein interactions. Although traditional affinity-based chemical proteomics approaches have made great progress in the identification of cellular targets and elucidation of MOAs of many bioactive molecules, nonspecific binding remains a major issue which may reduce the accuracy of target identification and may hamper the drug development process. Recently, quantitative proteomics approaches, namely, metabolic labeling, chemical labeling, or label-free approaches, have been implemented in target identification to overcome such limitations. In this review, we will summarize and discuss the recent advances in the application of various quantitative chemical proteomics approaches for the identification of targets of natural and traditional medicines.

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Zerumbone is a phytochemical with diverse biological activities ranging from anti-inflammatory to anti-cancer properties; however, to date the cellular targets of this important compound have remained elusive. Here we report the global protein target spectrum of zerumbone in living cancer cells using competitive activity-based protein profiling of a novel cell-permeable clickable probe, combined with quantitative mass spectrometry.

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Protein lipidation is unique amongst post-translational modifications (PTMs) in enabling direct interaction with cell membranes, and is found in every form of life. Lipidation is important in normal function and in disease, but its intricate interplay with disease context presents a challenging for drug development. Global whole-proteome profiling of protein lipidation lies beyond the range of standard methods, but is well-suited to metabolic tagging with small 'clickable' chemical reporters that do not disrupt metabolism and function; chemoselective reactions are then used to add multifunctional labels exclusively to tagged-lipidated proteins. This chemical proteomic technology has opened up the first quantitative whole-proteome studies of the known major classes of protein lipidation, and the first insights into their full scope in vivo.

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Histone deacetylase (HDAC) enzymes have been demonstrated as critical components in maintaining chromatin homeostasis, CNS development, and normal brain function. Evidence in mouse models links HDAC expression to learning, memory, and mood-related behaviors; small molecule HDAC inhibitor tool compounds have been used to demonstrate the importance of specific HDAC subtypes in modulating CNS-disease-related behaviors in rodents. So far, no direct evidence exists to understand the quantitative changes in HDAC target engagement that are necessary to alter biochemistry and behavior in a living animal. Understanding the relationship between target engagement and in vivo effect is essential in refining new ways to alleviate disease. We describe here, using positron emission tomography (PET) imaging of rat brain, the in vivo target engagement of a subset of class I/IIb HDAC enzymes implicated in CNS-disease (HDAC subtypes 1, 2, 3, and 6). We found marked differences in the brain penetrance of tool compounds from the hydroxamate and benzamide HDAC inhibitor classes and resolved a novel, highly brain penetrant benzamide, CN147, chronic treatment with which resulted in an antidepressant-like effect in a rat behavioral test. Our work highlights a new translational path for understanding the molecular and behavioral consequences of HDAC target engagement.

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A succinylation-specific photo-cross-linking peptide probe has been developed for the NAD(+)-dependent hydrolase Sirtuin 5. The probe, not only displayed robust labelling performance with purified Sirt5, but also enabled sensitive detection of the hydrolase in the presence of large excess of cellular proteins. It is anticipated that this probe, and future generations of it, will provide useful chemical tools for the functional analysis of Sirt5 and for the recently discovered PTM of lysine succinylation.

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Phytochemicals and their synthetic derivatives are making a significant contribution in modern drug discovery programs by targeting several human diseases, including cancer. Most of these natural compounds are often multitargeted in nature, which is generally a very desirable property for cancer therapy, as carcinomas typically involve dysregulation of multiple genes and associated cell-signaling pathways at various stages of initiation, progression and metastasis. Additionally, these natural agents generally have lower side-effects, are readily available and hence are cost effective. One such natural compound is zerumbone, a cyclic eleven-membered sesquiterpene, isolated from the tropical plant Zingiber zerumbet Smith that has attracted great attention recently for its potent anticancer activities in several tumor models. This review summarizes the data based on various in vitro and in vivo studies related to the effects of zerumbone on numerous pivotal molecular targets in cancer and its reported chemopreventive/therapeutic effects in different models of cancer.

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BACKGROUND: The rate of recovery of platelet function after discontinuation of P2Y(12) inhibitors depends on the reversibility of the antiplatelet effect and the extent of the on-treatment response. P2Y(12) inhibition increases the bleeding risk in patients requiring surgery. OBJECTIVES: To evaluate recovery of platelet function after discontinuation of ticagrelor vs. clopidogrel in stable coronary artery disease (CAD) patients with high levels of platelet inhibition (HPI) during the ONSET/OFFSET study. METHODS: Patients received aspirin 75-100 mg per day and either ticagrelor 90 mg twice-daily or clopidogrel 75 mg daily for 6 weeks. This subanalysis included patients with HPI after the last dose of maintenance therapy, defined as: inhibition of platelet aggregation (IPA) > 75% 4 h post-dose (ADP 20 µm, final extent); < 120 P2Y(12) reaction units 8 h post-dose (VerifyNow P2Y(12) assay); or platelet reactivity index < 50% 8 h post-dose (VASP-P assay). RESULTS: IPA > 75% was observed in 39 out of 47 ticagrelor-treated and 17 out of 44 clopidogrel-treated patients. The rate of offset of IPA over 4-72 h was greater with ticagrelor (IPA %/hour slope: -1.11 vs. -0.67 for clopidogrel; P < 0.0001). Mean IPA was significantly lower with ticagrelor than clopidogrel between 48 and 168 h post-dose (P < 0.01). Similar findings were observed with the other assays. The average time for IPA to decline from 30% to 10% was 50.8 h with ticagrelor vs. 110.4 h with clopidogrel. CONCLUSIONS: In patients with HPI, recovery of platelet function was more rapid after discontinuation of ticagrelor than clopidogrel leading to significantly greater platelet reactivity by 48 h after the last dose in the ticagrelor group.

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Of the thousands of known chemical reactions, a handful of reactions, called "click" reactions, stand out with features such as good chemoselectivity, good solvent compatibilities, modularity, minimum synthetic demands, bioorthogonality and high yields. Among them, the Cu(i)-catalyzed 1,3-dipolar cycloaddition reaction between azides and terminal alkynes has emerged as a powerful tool in chemical biology and proteomics. This perspective surveys the significant contributions of click chemistry in catalomics (a sub-area in chemical proteomics), with special emphasis on activity-based protein profiling (ABPP), posttranslational modifications (PTMs) and enzyme inhibitor developments.

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Two different strategies, namely a dialdehyde-based cross-linking and photo-affinity labeling, have been developed to generate small molecule activity-based probes (ABPs) for the Abelson (Abl) tyrosine kinase, of which probe 13, derived from the photo-affinity approach, showed specific labeling of Abl kinase present in a crude mammalian proteome.

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Synthesis of a novel unnatural amino acid (2-FMPT) for the solid-phase synthesis of peptide-based probes suitable for target-specific activity-based profiling of protein tyrosine phosphatases from crude proteomes is reported.

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Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl) tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potent inhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.

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A approximately 3500-member library of bidentate inhibitors against protein tyrosine phosphatases (PTPs) was rapidly assembled using click chemistry. Subsequent high-throughput screening had led to the discovery of highly potent (K(i) as low as 150 nM) and selective MptpB inhibitors, some of which represent the most potent MptpB inhibitors developed to date.

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A key challenge in current drug discovery is the development of high-throughput (HT) amenable chemical reactions that allow rapid synthesis of diverse chemical libraries of enzyme inhibitors. The Cu(I)-catalyzed, 1,3-dipolar cycloaddition between an azide and an alkyne, better known as "click chemistry", is one such method that has received the most attention in recent years. Despite its popularity, there is still a lack of robust and efficient chemical strategies that give access to diverse libraries of azide-containing building blocks (key components in click chemistry). We report herein a highly robust and efficient strategy for high-throughput synthesis of a 325-member azide library. The method is highlighted by its simplicity and product purity. The utility of the library is demonstrated with the subsequent "click" synthesis of the corresponding bidentate inhibitors against PTP1B.

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