Structure-Activity Relationship Studies of Antimalarial Proteasome Inhibitors─Part II.

With increasing reports of resistance to artemisinins and artemisinin-combination therapies, targeting the proteasome is a promising strategy for antimalarial development. We recently reported a highly selective proteasome inhibitor with anti-malarial activity in the humanized mouse model. To balance the permeability of the series of macrocycles with other drug-like properties, we conducted further structure-activity relationship studies on a biphenyl ether-tethered macrocyclic scaffold.

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.

With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. , the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa.

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors.

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S.

Macrocyclic Peptides that Selectively Inhibit the Proteasome.

Treatment of tuberculosis (TB) currently takes at least 6 months. Latent (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs.

Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions.

Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase is a metabolic and antioxidant enzyme critical for mycobacterial growth and survival in mice.

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P.

Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations.

The integrin αVβ3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761.

Pharmacological evaluation of a novel corticotropin-releasing factor 1 receptor antagonist T-3047928 in stress-induced animal models in a comparison with alosetron.

Background: The major symptoms of irritable bowel syndrome (IBS) are changes in bowel habits and abdominal pain. Psychological stress is the major pathophysiological components of IBS. Corticotropin-releasing factor (CRF) is a well-known integrator in response to psychological stress.

Identification of a novel series of potent and selective CCR6 inhibitors as biological probes.

CCR6 has been implicated in both autoimmune diseases and non-autoimmune diseases. Thus, inhibition of CCR6-dependent cell migration is an attractive strategy for their treatment. An orally available small molecule inhibitor of CCR6 could therefore be a useful biological probe for the pathophysiological studies.

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin.

Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel series of G protein-coupled receptor 52 (GPR52) agonists.

G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders.

Discovery of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazoles as novel class of corticotropin releasing factor 1 receptor antagonists.

A new class of corticotropin releasing factor 1 (CRF) receptor antagonists characterized by a tricyclic core ring was designed and synthesized. Novel tricyclic derivatives 2a-e were designed as CRF receptor antagonists based on conformation analysis of our original 2-anilinobenzimidazole CRF receptor antagonist. The synthesized tricyclic derivatives 2a-e showed CRF receptor binding activity with IC values of less than 400 nM, and the 1,2,3,4-tetrahydropyrimido-[1,2-a]benzimidazole derivative 2e was selected as a lead compound with potent in vitro CRF receptor binding activity (IC = 7.

Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aβ-Fibrinogen Interaction and Aβ-Induced Contact System Activation.

Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and β-amyloid (Aβ), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since Aβ oligomers have a much stronger affinity for fibrinogen than Aβ monomers, we tested whether amyloid aggregation inhibitors could block the Aβ-fibrinogen interaction and found that some Aβ aggregation inhibitors showed moderate inhibitory efficacy against this interaction.

Publisher Correction: Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.

The previously published version of this Article contained errors in Fig. 6. In panel h the units of the x axis were incorrectly given as mM and should have been given as µM.

Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.

Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon binding double-stranded DNA, cyclic GMP-AMP synthase synthesizes a cyclic dinucleotide that initiates an inflammatory cellular response. Mouse studies that recapitulate causative mutations in the autoimmune disease Aicardi-Goutières syndrome demonstrate that ablating the cyclic GMP-AMP synthase gene abolishes the deleterious phenotype.

Characterization of CRF receptor antagonists with differential peripheral vs central actions in CRF challenge in rats.

The aim of this study was to investigate peripheral and central roles of corticotropin-releasing factor (CRF) in endocrinological and behavioral changes. Plasma adrenocorticotropin (ACTH) concentration was measured as an activity of hypothalamic-pituitary-adrenal (HPA) axis. As behavioral changes, locomotion and anxiety behavior were measured after CRF challenge intravenously (i.

Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action.

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency.

Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists.

G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (4u; half maximal effective concentration (EC)=75nM, maximal response (E)=122%) starting from a high-throughput screening hit 3 (EC=470nM, E=56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists.

Rejuvenation of mucosal immunosenescence by adipose tissue-derived mesenchymal stem cells.

Age-associated alterations in the mucosal immune system are generally termed mucosal immunosenescence. The major change seen in the aged mucosa is a failure to elicit an antigen-specific secretory IgA (SIgA) antibody response, which is a central player for host defense from various pathogens at mucosal surfaces. In this regard, it would be a first priority to compensate for mucosal dysregulation in the elderly in order to maintain their health in aging.

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF receptor antagonist.

Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF) receptor (IC=9.5nM) and in vitro antagonistic activity (IC=88nM) but is rapidly metabolized by human hepatic microsomes (182μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity.

Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor antagonists.

A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles.

Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen.

The majority of patients with Alzheimer disease (AD) suffer from impaired cerebral circulation. Accumulating evidence suggests that fibrinogen, the main protein component of blood clots, plays an important role in this circulatory dysfunction in AD. Fibrinogen interacts with β-amyloid (Aβ), forming plasmin-resistant abnormal blood clots, and increased fibrin deposition is found in the brains of AD patients and mouse models.

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.

Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice.

It has been shown that adipose-derived mesenchymal stem cells (AMSCs) can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI) immune system has been well documented.