Target-based discovery of a broad-spectrum flukicide.

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases-for example, the parasitic blood fluke infection schistosomiasis-are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPM), in Fasciola species.

Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types.

Inhibition of the bromodomain and extraterminal domain (BET) protein family is a potential strategy to prevent and treat diabetes; however, the clinical use of BET bromodomain inhibitors (BETis) is associated with adverse effects. Here, we explore a strategy for targeting BETis to β cells by exploiting the high-zinc (Zn) concentration in β cells relative to other cell types. We report the synthesis of a novel, Zn-chelating derivative of the pan-BETi (+)-JQ1, (+)-JQ1-DPA, in which (+)-JQ1 was conjugated to dipicolyl amine (DPA).

The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago.

The Anthelmintic Activity of Praziquantel Analogs Correlates with Structure-Activity Relationships at TRPM Orthologs.

The anthelmintic drug praziquantel remains a key clinical therapy for treating various diseases caused by parasitic flatworms. The parasite target of praziquantel has remained undefined despite longstanding usage in the clinic, although a candidate ion channel target, named TRPM, has recently been identified. Intriguingly, certain praziquantel derivatives show different activities against different parasites: for example, some praziquantel analogs are considerably more active against cestodes than against schistosomes.

Target-based discovery of a broad spectrum flukicide.

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases - for example, the parasitic blood fluke infection, schistosomiasis - are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus .

Mu-opioid receptor selective superagonists produce prolonged respiratory depression.

Synthetic opioids are increasingly challenging to combat the opioid epidemic and act primarily at opioid receptors, chiefly the G protein-coupled receptor (GPCR) μ-opioid receptor (MOR), which signals through G protein-dependent and β-arrestin pathways. Using a bioluminescence resonance energy transfer (BRET) system, we investigate GPCR-signaling profiles by synthetic nitazenes, which are known to cause overdose and death due to respiratory depression. We show that isotonitazene and its metabolite, -desethyl isotonitazene, are very potent MOR-selective superagonists, surpassing both DAMGO G protein and β-arrestin recruitment activity, which are properties distinct from other conventional opioids.

Molecular and cellular basis of praziquantel action in the cardiovascular system.

The anthelmintic drug praziquantel (PZQ) causes contraction of parasitic schistosomes as well as constriction of blood vessels within the mesenteric vasculature of the host where the adult blood flukes reside. The contractile action of PZQ on the vasculature is mediated by the activation of host serotonergic 5-HT receptors (5-HTRs). However, the molecular basis for PZQ interaction with these targets and the location of these 5-HT receptors in the vessel wall have not been experimentally defined.

Natural variation in the binding pocket of a parasitic flatworm TRPM channel resolves the basis for praziquantel sensitivity.

The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A schistosome target for PZQ was recently identified- a transient receptor potential ion channel in the melastatin subfamily (TRPM)-however, little is known about the properties of TRPM in other parasitic flatworms. Here, TRPM orthologs were scrutinized from all currently available parasitic flatworm genomes.

Fluorinated triphenylphosphonium analogs improve cell selectivity and detection of mito-metformin.

Triphenylphosphonium (TPP) conjugated compounds selectively target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. To date, studies have focused on modifying either the linker or the cargo of TPP-conjugated compounds. Here, we investigated the biological effects of direct modification to TPP to improve the efficacy and detection of mito-metformin (MMe), a TPP-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells.

Identification of a dihydropyridine scaffold that blocks ryanodine receptors.

Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca homeostasis in scenarios involving RyR dysfunction.

Trisubstituted 1,3,5-Triazines: The First Ligands of the sY12-Binding Pocket on Chemokine CXCL12.

CXCL12, a CXC-type chemokine, binds its receptor CXCR4, and the resulting signaling cascade is essential during development and subsequently in immune function. Pathologically, the CXCL12-CXCR4 signaling axis is involved in many cancers and inflammatory diseases and thus has sparked continued interest in the development of therapeutics. Small molecules targeting CXCR4 have had mixed results in clinical trials.

Substituted Imidazoline Synthesis: A Diastereo- and Enantioselective aza-Henry Route to a Human Proteasome Modulator.

The first enantio- and diastereoselective synthesis of Tepe's human proteasome modulator is described. Routes to this and other highly substituted chiral imidazolines generally produce racemic material. Key to the route disclosed here is a gram-scale -selective aza-Henry reaction of an α-alkyl α-nitro ester nucleophile, catalyzed by a Bis(Amidine) [BAM] chiral proton complex, delivering the key intermediate in high yield as a single stereoisomer.

Development of activity-based probes for the protein deacylase Sirt1.

Sirtuins are NAD-dependent protein deacylases that remove acyl modifications from acyl-lysine residues, resulting in essential cellular signaling. Recognized for their role in lifespan extension, humans encode seven sirtuin isoforms (Sirt1-7), and loss of sirtuin deacylase activity is implicated in many aging-related diseases. Despite being intriguing therapeutic targets, cellular studies of sirtuins are hampered by the lack of chemical probes to measure sirtuin activity independent of sirtuin protein levels.

Diastereo- and enantioselective additions of α-nitro esters to imines for -α,β-diamino acid synthesis with α-alkyl-substitution.

The discovery that a -symmetric bis(AMidine) [BAM] catalyst promotes an -selective addition of α-substituted α-nitro esters to imines is described, providing α-substituted α,β-diamino ester products with high diastereo- and enantioselectivity. When compared to the function of a BAM catalyst reported previously, the pair offer a rare example of diastereodivergence using a bifunctional Brønsted acid-base organocatalyst.

Adaptation of a small-molecule hydrogen-bond donor catalyst to an enantioselective hetero-Diels-Alder reaction hypothesized for brevianamide biosynthesis.

Chiral diamine-derived hydrogen-bond donors were evaluated for their ability to effect stereocontrol in an intramolecular hetero-Diels-Alder (HDA) reaction hypothesized in the biosynthesis of brevianamides A and B. Collectively, these results provide proof of principle that small-molecule hydrogen-bond catalysis, if even based on a hypothetical biosynthesis construct, holds significant potential within enantioselective natural product synthesis.

Enantio- and periselective nitroalkene Diels-Alder reaction.

The periselective Diels-Alder reaction of 5-substituted pentamethylcyclopentadienes and nitroethylene has been realized by helical-chiral hydrogen bond donor catalysts. To our knowledge, this represents the first asymmetric catalytic nitroalkene Diels-Alder reaction via activation of nitroalkene, and thus establishes its proof-of-principle.