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Clinical diagnosis of Alzheimer’s disease (AD) is based on symptoms; however, the challenge is to diagnose AD at the preclinical stage with the application of biomarkers and initiate early treatment (still not widely available). Currently, cerebrospinal fluid (CSF) amyloid-ß 42 (Aß42) and tau are used in the clinical diagnosis of AD; nevertheless, blood biomarkers (Aß42and tau) are less predictive. Amyloid-positron emission tomography (PET) imaging is an advancement in technology that uses approved radioactive diagnostic agents (florbetapir, flutemetamol, or florbetaben) to estimate Aß neuritic plaque density in adults with cognitive impairment evaluated for AD and other causes of cognitive decline. There is no cure for AD to date—the disease progression cannot be stopped or reversed; approved pharmacological agents (donepezil, galantamine, and rivastigmine; memantine) provide symptomatic treatment. However, the disease-modifying therapies are promising; aducanumab and CAD106 are in phase III trials for the early stages of AD. In conclusion, core CSF biomarkers reflect pathophysiology of AD in the early and late stages; the application of approved radiotracers have potential in amyloid-PET brain imaging to detect early AD.

ABSTRACTAging is associated with a gradual decline of cellular proteostasis, giving rise to devastating protein misfolding diseases, such as Alzheimer disease (AD) or Parkinson disease (PD). These diseases often exhibit a complex pathology involving non-cell autonomous proteotoxic effects, which are still poorly understood. Using Caenorhabditis eleganswe investigated how local protein misfolding is affecting neighboring cells and tissues showing that misfolded PD-associated SNCA/α-synuclein is accumulating in highly dynamic endo-lysosomal vesicles. Irrespective of whether being expressed in muscle cells or dopaminergic neurons, accumulated proteins were transmitted into the hypodermis with increasing age, indicating that epithelial cells might play a role in remote degradation when the local endo-lysosomal degradation capacity is overloaded. Cell biological and genetic approaches revealed that inter-tissue dissemination of SNCA was regulated by endo- and exocytosis (neuron/muscle to hypodermis) and basement membrane remodeling (muscle to hypodermis). Transferred SNCA conformers were, however, inefficiently cleared and induced endo-lysosomal membrane permeabilization. Remarkably, reducing INS (insulin)-IGF1 (insulin-like growth factor 1) signaling provided protection by maintaining endo-lysosomal integrity. This study suggests that the degradation of lysosomal substrates is coordinated across different tissues in metazoan organisms. Because the chronic dissemination of poorly degradable disease proteins into neighboring tissues exerts a non-cell autonomous toxicity, this implies that restoring endo-lysosomal function not only in cells with pathological inclusions, but also in apparently unaffected cell types might help to halt disease progression.Abbreviations: AD: Alzheimer disease; BM: basement membrane; BWM: body wall muscle; CEP: cephalic sensilla; CLEM: correlative light and electron microscopy; CTNS-1: cystinosin (lysosomal protein) homolog; DA: dopaminergic; DAF-2: abnormal dauer formation; ECM: extracellular matrix; FLIM: fluorescence lifetime imaging microscopy; fps: frames per second; GFP: green fluorescent protein; HPF: high pressure freezing; IGF1: insulin-like growth factor 1; INS: insulin; KD: knockdown; LMP: lysosomal membrane permeabilization; MVB: multivesicular body; NOC: nocodazole; PD: Parkinson disease; RFP: red fluorescent protein; RNAi: RNA interference; sfGFP: superfolder GFP; SNCA: synuclein alpha; TEM: transmission electron microscopy; TNTs: tunneling nanotubes; TCSPC: time correlated single photon counting; YFP: yellow fluorescent protein.

ABSTRACTTwo PlasmodiumPI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivotesting as causal prophylactic and radical-cure agents for Plasmodium cynomolgisporozoite-infected rhesus macaques, based on their in vitroactivity against liver stages. Animals were infected with P. cynomolgisporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our in vitrodata. These findings indicate that PlasmodiumPI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer in vitroculture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure in vivo.

KAE609 [(1′R,3′S)-5,7′-dichloro-6′-fluoro-3′-methyl-2′,3′,4′,9′-tetrahydrospiro[indoline-3,1′-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. After oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Among the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1,2-acyl shift to form a ring expansion metabolite M37. The in vitro metabolism of KAE609 in hepatocytes was investigated to understand this novel biotransformation. The metabolism of KAE609 was qualitatively similar across the species studied; thus, further investigation was conducted using human recombinant cytochrome P450 enzymes. The ring expansion reaction was found to be primarily catalyzed by cytochrome P450 (CYP) 3A4 yielding M37. M37 was subsequently oxidized to M18 by CYP3A4 and hydroxylated to M23 primarily by CYP1A2. Interestingly, M37 was colorless, whereas M18 and M23 showed orange yellow color. The source of the color of M18 and M23 was attributed to their extended conjugated system of double bonds in the structures.

Laetirobin, isolated from a parasitic fungus host–plant relationship, was synthesized in six practical steps with an overall yield of 12 % from commercially available 2,4‐dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)‐mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem‐diaryl alkene precursors. Preliminary structure–activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).

(±)-Laetirobin (1) was isolated as a cytostatic lead from Laetiporus sulphureusgrowing parasitically on the black locust tree, Robinia pseudoacacia, by virtue of a reverse-immunoaffinity system. Using an LC/MS procedure, milligram quantities of (±)-laetirobin (1) were obtained, and the structure of 1was elucidated by X-ray crystallography and confirmed by NMR spectroscopy. Preliminary cellular studies indicated that (±)-laetirobin (1) rapidly enters in tumor cells, blocks cell division at a late stage of mitosis, and invokes apoptosis.

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum(Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963(1), which demonstrates potent cellular activity against Pf3D7 (EC50= 0.006 μM) and achieves “artemisinin-like” kill kinetics in vitrowith a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963(1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963(1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963(1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.

Paclitaxel added to angiographic contrast medium (CM) has been shown to inhibit restenosis in the porcine coronary overstretch model. This study determined early local tissue concentrations after the administration of different paclitaxel doses and preparations.

NITD-688, a pan-serotype dengue virus inhibitor, is effective in mice and is well tolerated with favorable pharmacokinetics in animal models.

Natural productlaetirobin, isolated from a parasitic fungus host–plant relationship, is synthesized in six practical steps with an overall yield of 12 % from commercially available 2,4‐dihydroxyacetophenone. M. J. Lear et al. provide preliminary structure–activity relationship data between the isomeric [4+2] and [5+2] tetramers that reveal that only the natural product possesses promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis). For further details, turn to their Full Paper on page 342 ff.