ライフサイエンスコーパス: GNE

1 GNE (UDP-GlcNAc 2-epimerase/ManNAc kinase) myopathy is a

2 GNE deficiency may affect levels of UDP-GlcNAc, a key me

3 GNE harbors two enzymatic activities required for biosyn

4 GNE myopathy is a rare recessive myopathy associated wit

5 GNE Myopathy is a rare recessively inherited neuromuscul

6 GNE myopathy is an autosomal recessive muscle disease ca

7 GNE myopathy is an important diagnosis to consider in pa

8 GNE-6640 and GNE-6776 interact with acidic residues that

9 GNE-KLH (keyhole limpet hemocyannin) was found to elicit

10 Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class

11 Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective,

12 is effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stab

13 The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are

14 Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailab

15 The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK)

16 However, little is known about GNE myopathy in Europe where the prevalence is thought t

17 caine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenov

18 he rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhib

19 GNE-6640 and GNE-6776 interact with acidic residues that mediate hydr

20 Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12 A distant from th

21 nt of selective USP7 inhibitors GNE-6640 and GNE-6776.

22 scovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance of

23 Mutations to both GNE domains are linked to GNE myopathy.

24 alic acid metabolism, that are influenced by GNE.

25 Notably, N-linked glycans produced by GNE-deficient cells displayed enhanced binding to galect

26 The most advanced delta-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dio

27 c siRNAs specifically targeting the dominant GNE mutation c.797G>A (p.R266Q) in sialuria fibroblasts.

28 sociated with mutations in titin, dysferlin, GNE, desmin and myosin.

29 s S-nitrosylation, accounts for the enhanced GNE that we have observed and that has been previously o

30 nitrosylation of Ras might lead to enhanced GNE.

31 O2 mediates Ras guanine nucleotide exchange (GNE) by conversion of Ras-bound GDP into an unstable 5-n

32 hown to promote guanine nucleotide exchange (GNE) on Ras and increase cellular Ras-GTP levels, but th

33 actions and Ras-guanine nucleotide exchange (GNE).

34 perfamily GTPases, as NO/O2 also facilitates GNE on the redox-active Rap1A and Rab3A GTPases.

35 Furthermore, GNE deficiency and glucose supplementation acted indepen

36 A cocaine-like hapten GNE and a cocaine transition-state analogue GNT were use

37 tion to the three previously described human GNE isoforms (hGNE1-hGNE3), our database and polymerase

38 ulated, in hyposialylated muscles from human GNE myopathy patients and model mice.

39 unctional and regulatory mechanisms of human GNE and may contribute to further elucidating the pathol

40 izing disease-causing mutations in the human GNE gene that give rise to sialuria, hereditary inclusio

41 hology and treatment strategies of the human GNE-opathies sialuria and hereditary inclusion body myop

42 e is diminished SWV and muscle anisotropy in GNE-related myopathy.

43 ng to galectin-1, indicating that changes in GNE activity can alter affinity of cell-surface glycopro

44 cle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzym

45 GNE myopathy is associated with mutations in GNE.

46 oxidative stress as a therapeutic target in GNE myopathy.

47 G2019S LCLs with the LRRK2 kinase inhibitor GNE-7915, either prevented or restored mtDNA damage to c

48 Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protecti

49 ion of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical speci

50 the development of selective USP7 inhibitors GNE-6640 and GNE-6776.

51 for UDP-GlcNAc 2-epimerase/ManNAc 6-kinase (GNE) beyond controlling flux into the sialic acid biosyn

52 UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) catalyzes the first two committed steps in sialic a

53 imerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), result in hereditary inclusion body myopathy (

54 deposition of maternal gne mRNA and maternal GNE protein at the earliest embryonic stage, emphasizing

55 levels, but the process by which NO-mediated GNE occurs is not clear.

56 eaction, a H+, may contribute to NO-mediated GNE.

57 Advancement of GNE-7915 into rodent and higher species toxicity studies

58 To investigate other potential effects of GNE mutations, we compared sialic acid production in cel

59 s GM3 and GD3 also changed the expression of GNE and led to reduced ST3Gal5 and ST8Sia1 mRNA levels,

60 ines expressing wild type or mutant forms of GNE.

61 rs culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and sel

62 The resultant loss of feedback inhibition of GNE-epimerase activity by CMP-sialic acid causes excessi

63 Feedback inhibition of GNE-epimerase activity by CMP-sialic acid recovered afte

64 We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent a

65 Conversely, down-regulation of GNE by RNA interference methods had the opposite, but co

66 missense mutations in the allosteric site of GNE, coding for the rate-limiting enzyme of sialic acid

67 alic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degen

68 al, continuous administration to 50-week-old GNE myopathy mice for 30 weeks.

69 Most of the current information on GNE myopathy has been obtained through studies of Jewish

70 in of Raf (a downstream effector of Ras), or GNE rates relative to non-nitrosylated Ras.

71 50 years) with genetically and biopsy-proved GNE-related myopathy and five healthy volunteers (three

72 y proposed a mechanism of NO/O2-mediated Ras GNE, in which *NO2, formed by the reaction of NO with O2

73 adical-based mechanism of NO/O2-mediated Ras GNE.

74 likely to be involved in the NO-mediated Ras GNE.

75 thiyl radical intermediate that promotes Ras GNE, we have also postulated that another byproduct of t

76 creased ganglioside levels (e.g. recombinant GNE and exogenous gangliosides) led to reduced prolifera

77 Overexpression of recombinant GNE in human embryonic kidney (HEK AD293) cells led to a

78 ion to exhibiting low levels of sialylation, GNE-deficient cells produced distinct N-linked glycan st

79 scle atrophy and degeneration in symptomatic GNE myopathy mice.

80 to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2

81 Control experiments ensured that GNE-mediated changes in sialyltransferase expression and

82 Our results provide evidence that GNE myopathy can be treated even at a progressive stage

83 Our findings imply that GNE is subject to evolutionary mechanisms to improve cel

84 Structural studies reveal that GNE-6640 and GNE-6776 non-covalently target USP7 12 A di

85 and mass spectrometry analysis revealed that GNE deficiency is associated with unanticipated effects

86 All patients harbouring mutations in the GNE gene were recruited for our study.

87 muscular disorder caused by mutations in the GNE gene, which codes for the key enzyme in the metaboli

88 fied 26 patients harbouring mutations in the GNE gene.

89 nt cohorts carrying founder mutations in the GNE gene.

90 Genetic defects of the GNE gene which encodes a critical bifunctional enzyme fo

91 diagnosis is confirmed by sequencing of the GNE gene.

92 Cellular responses to the GNE-mediated changes in ST3Gal5 and ST8Sia1 expression a

93 enzyme for sialic acid biosynthesis, lead to GNE myopathy, a disease manifesting with progressive mus

94 Mutations to both GNE domains are linked to GNE myopathy.

95 sporadic inclusion body myositis is unknown, GNE myopathy is associated with mutations in GNE.

96 Here we utilize GNE-617, a small molecule inhibitor of NAMPT, a rate-lim

97 To elucidate whether GNE myopathy is treatable at a progressive stage of the

98 suggest an unanticipated mechanism by which GNE activity might affect signaling through cell-surface

99 The process by which GNE mutations lead to myopathy is not well understood.

100 Patients with GNE myopathy, a progressive and debilitating disease cau

101 a precursor of sialic acid) in patients with GNE myopathy.

102 accurate diagnosis is made in patients with GNE myopathy.

103 SWV was significantly lower in patients with GNE-related myopathy than in control subjects (P < .02).

104 muscles were evaluated in the patients with GNE-related myopathy, and the gastrocnemius, vastus late

105 essment of disease activity in patients with GNE-related myopathy.

106 d preload were examined in the patients with GNE-related myopathy.