Dataset Information

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency.

ABSTRACT: Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.

SUBMITTER: Kung C

PROVIDER: S-EPMC5609468 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency.

Kung Charles C Hixon Jeff J Kosinski Penelope A PA Cianchetta Giovanni G Histen Gavin G Chen Yue Y Hill Collin C Gross Stefan S Si Yaguang Y Johnson Kendall K DeLaBarre Byron B Luo Zhiyong Z Gu Zhiwei Z Yao Gui G Tang Huachun H Fang Cheng C Xu Yingxia Y Lv Xiaobing X Biller Scott S Su Shin-San Michael SM Yang Hua H Popovici-Muller Janeta J Salituro Francesco F Silverman Lee L Dang Lenny L

Blood 20170731 11

Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data il ...[more]

PMID: 28760888

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Project description:Malaria remains a major world public health problem, contributing to poverty and inequality. It is urgent to find new efficacious tools with few adverse effects. Malaria has selected red blood cell (RBC) alterations linked to resistance against infection, and understanding the protective mechanisms involved may be useful for developing host-directed tools to control Plasmodium infection. Pyruvate kinase deficiency has been associated with resistance to malaria. Pyruvate kinase-deficient RBCs display an increased concentration of 2,3-diphosphoglycerate (2,3-DPG). We recently showed that 2,3-DPG impacts in vitro intraerythrocytic parasite growth, induces a shift of the metabolic profile of infected cells (iRBCs), making it closer to that of noninfected ones (niRBCs), and decreases the number of parasite progenies that invade new RBCs. As an increase of 2,3-DPG content may also have an adverse effect on RBC membrane and, consequently, on the parasite invasion, in this study, we explored modifications of the RBC morphology, biomechanical properties, and RBC membrane on Plasmodium falciparum in vitro cultures treated with 2,3-DPG, using atomic force microscopy (AFM)-based force spectroscopy and other experimental approaches. The presence of infection by P. falciparum significantly increased the rigidity of parasitized cells and influenced the morphology of RBCs, as parasitized cells showed a decrease of the area-to-volume ratio. The extracellular addition of 2,3-DPG also slightly affected the stiffness of niRBCs, making it more similar to that of infected cells. It also changed the niRBC height, making the cells appear more elongated. Moreover, 2,3-DPG treatment influenced the cell surface charge, becoming more negative in treated RBCs than in untreated ones. The results indicate that treatment with 2,3-DPG has only a mild effect on RBCs in comparison with the effect of the presence of the parasite on the host cell. 2,3-DPG is an endogenous host metabolite, which may, in the future, originate a new antimalarial tool with few adverse effects on noninfected cells.

Dataset Information

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency.

Publications

AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency.

Similar Datasets

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