Author: Aoki, Junken ; Inoue, Asuka ; Hamaoka-Tamura, Yuho ; Saito, Michiko ; Oka, Masumi ; Kato, Shinichi ; Matsuno, Kenji ; Akaki, Sohta ; Tanaka, Satoshi ; Ohno, Osamu ; Terasaki, Maho ; Furuta, Kazuyuki

Mast cell stabilizers, including disodium cromoglycate (DSCG), were found to have potential as the agonists of an orphan G protein-coupled receptor, GPR35, although it remains to be determined whether GPR35 is expressed in mast cells and involved in suppression of mast cell degranulation. Our purpose in this study is to verify the expression of GPR35 in mast cells and to clarify how GPR35 modulates the degranulation. We explored the roles of GPR35 using an expression system, a mast cell line constitutively expressing rat GPR35, peritoneal mast cells, and bone marrow-derived cultured mast cells. Immediate allergic responses were assessed using the IgE-mediated passive cutaneous anaphylaxis (PCA) model. Various known GPR35 agonists, including DSCG and newly designed compounds, suppressed IgE-mediated degranulation. GPR35 was expressed in mature mast cells but not in immature bone marrow-derived cultured mast cells and the rat mast cell line. Degranulation induced by antigens was significantly downmodulated in the mast cell line stably expressing GPR35. A GPR35 agonist, zaprinast, induced a transient activation of RhoA and a transient decrease in the amount of filamentous actin. GPR35 agonists suppressed the PCA responses in the wild-type mice but not in the GPR35^-/- mice. These findings suggest that GPR35 should prevent mast cells from undergoing degranulation induced by IgE-mediated antigen stimulation and be the primary target of mast cell stabilizers. SIGNIFICANCE STATEMENT: The agonists of an orphan G protein-coupled receptor, GPR35, including disodium cromoglycate, were found to suppress degranulation of rat and mouse mature mast cells, and their antiallergic effects were abrogated in the GPR35^-/- mice, indicating that the primary target of mast cell stabilizers should be GPR35.

01 Dec 2023·Biochimica et Biophysica Acta (BBA) - General Subjects

Screening for new inhibitors of the human Mitochondrial Pyruvate Carrier and their effects on hepatic glucose production and diabetes

Article

Author: Martinou, Jean-Claude ; Li, Lingzi ; Jiménez-Sánchez, Cecilia ; Maechler, Pierre ; Herzig, Sébastien

BACKGROUNDThe mitochondrial pyruvate carrier (MPC) is a protein complex composed of two subunits, MPC1 and MPC2. This carrier is at the interface between glycolysis and mitochondrial metabolism and plays an essential role in hepatic glucose production.METHODSHere we describe an in vitro screen for small molecule inhibitors of the MPC using a strain of Lactococcus lactis that has been engineered to co-express the two subunits of the human MPC and is able to import exogenous 14C-pyruvate. We then tested the top candidates for potential antidiabetic effects through the repression of gluconeogenesis.RESULTSBy screening the Prestwick compound library of 1'200 drugs approved by the Food and Drug Administration for inhibitors of pyruvate uptake, twelve hit molecules were identified. In a secondary screen, the most potent inhibitors were found to inhibit pyruvate-driven oxygen consumption in mouse C2C12 muscle cells. Assessment of gluconeogenesis showed that Zaprinast, as well as the established MPC inhibitor UK5099, inhibited in vitro and in vivo hepatic glucose production. However, when tested acutely in mice without the administration of gluconeogenic substrates, MPC inhibitors raised blood glucose levels, pointing to liver-independent effects. Furthermore, chronic treatment with Zaprinast failed to correct hyperglycemia in both lean and obese diabetic mouse models.CONCLUSIONSNew MPC inhibitors have been identified, showing inhibitory effects on hepatic glucose production.GENERAL SIGNIFICANCEFor potential antidiabetic applications, MPC inhibitors should target the liver without undesired inhibition of mitochondrial pyruvate metabolism in the skeletal muscles or pancreatic beta-cells in order to avoid dual effects on glycemia.

01 Feb 2022·Journal of Biological ChemistryQ2 · BIOLOGY

Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice

Q2 · BIOLOGY

Article

Author: Hegazy, Lamees ; Hodges, Wesley T ; McCommis, Kyle S ; Griffett, Kristine ; Jarasvaraparn, Chaowapong ; Cho, Kevin ; Patti, Gary J ; Chen, Yana ; Elgendy, Bahaa ; Finck, Brian N ; Gill, Lauren E ; Ferguson, Daniel ; Ilagan, Ma Xenia G

The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the antidiabetic effects of zaprinast and 7ACC2, small molecules which have been reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer-based MPC reporter assay (reporter sensitive to pyruvate) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic-euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used reporter sensitive to pyruvate to screen a chemical library of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors.

100 Deals associated with zaprinast

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Preclinical	JP	Pfizer Japan, Inc.	17 Aug 2006
Rhinitis	Preclinical	JP	Pfizer Japan, Inc.	17 Aug 2006

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