Anti-ORAI1 antibody DS-2741a, a specific CRAC channel blocker, shows ideal therapeutic profiles for allergic disease via suppression of aberrant T-cell and mast cell activation.

ORAI1 constitutes the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, which is responsible for store-operated calcium entry into lymphocytes. It is known that ORAI1 is essential for the activation of T cells and mast cells and is considered to be a potent therapeutic target for autoimmune and allergic diseases. Here, we obtained a new humanized antibody, DS-2741a, that inhibits ORAI1 function.

Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor.

G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84.

Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro.

An orphan G-protein-coupled receptor, T cell death-associated gene 8 (TDAG8) which has been reported to be a proton sensor, inhibits the production of pro-inflammatory cytokines induced by extracellular acidification. Recently, we have found that TDAG8 knockout mice showed significant exacerbation in various immune-mediated inflammation disease models. To elucidate the role of TDAG8, we screened an in-house library to find compounds which have a profile as a TDAG8 agonist using a cyclic adenosine 5'-monophosphate assay.

Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells.

T cell death-associated gene 8 (TDAG8) is a G-protein-coupled receptor identified by differential mRNA display during thymocyte apoptosis induced by T cell receptor engagement. To examine the physiological role of an orphan G-protein-coupled receptor TDAG8 in inflammation, we studied various immune-mediated inflammatory disease models using TDAG8-deficient mice. We found that TDAG8-deficient mice showed significant exacerbation of anti-type II collagen antibody-induced arthritis and delayed-type hypersensitivity, and showed a slight exacerbation of collagen-induced arthritis.

A humanized anti-human Fas antibody, R-125224, induces apoptosis in type I activated lymphocytes but not in type II cells.

Fas-mediated apoptosis plays an important role in the immune system, including the elimination of autoreactive lymphoid cells. The Fas-mediated signaling pathway is classified into two types, type I and type II, in human lymphoid cell lines. We investigated whether a humanized anti-human Fas mAb, R-125224, has cell selectivity in induction of apoptosis.

The Us3 protein kinase of herpes simplex virus 1 blocks apoptosis and induces phosporylation of the Bcl-2 family member Bad.

Viruses have evolved different strategies to interfere with apoptotic pathways in order to halt cellular responses to infection. The herpes simplex virus 1 (HSV-1) Us3 open-reading frame encodes a serine/threonine protein kinase that participates in the inhibition of apoptosis induced by virus infection and other stress agents. Previous studies have shown that Us3 counteracts the virus-induced activation of caspase-3 by acting at a premitochondrial stage.

Anti-HIV-1 activities and pharmacokinetics of new arylpiperazinyl fluoroquinolones.

Anti-HIV-1 activities and pharmacokinetics of a series of novel arylpiperazinyl fluoroquinolones are reported. Modification at the C-8 position with a trifluoromethyl group was superior to that with a difluoromethoxy group to achieve higher anti-HIV-1 activity. Two compounds studied exhibited quite high anti-HIV-1 activities (IC(50)<50 nM) in vitro and high bioavailabilities (BA>90%) in monkeys.