66 research outputs found
Enzyme enhancement therapy through non-competitive pharmacological chaperones
Pharmacological chaperones, Chemical chaperones
,
Enzyme e
n-
hancement
therapy, GM1, Gangliosidosis, Morqui B, Lysosomal Storage Disease,
Lysosomal Storage DisordersMost Pharmacological chaperones (PCâs) described until now are
substrate analogues which bind to the active site of the target protein. C
ons
e-
quently, such PCâs also inhibit the target protein at higher concentrations thus
rendering a narrow therapeutic window and have poor drug-like properties.
Through our proprietary technology platform SEE-Txâą, we identify a new
generation of non-substrate competitive pharmacological chaperones which p
o-
tentially offer a much broader therapeutic window. Whatâs more, such co
m-
pounds are not substrate analogues, thus presenting much better drug-like pro
p-
erties, particularly for indications with CNS involvement. Here we present our
methodology to identify non-competitive pharmacological chaperones applied
to the enzyme beta-galactosidase, whose deficiency is related with GM1
Gangliosidosis and Morquio B.Postprint (published version
The effects of neck flexion on cerebral potentials evoked by visual, auditory and somatosensory stimuli and focal brain blood flow in related sensory cortices
Yolk proteins in the giant freshwater prawn, <i>Macrobrachium rosenbergii</i>: Determination of amino acid sequence and site of production
Molecular cloning and expression of corticotropin-releasing hormone and urotensin I in the medaka, <i>Oryzias latipes</i>
Changes in Immunoglobulin Producing Cells in Response to Gonadal Maturation in Rainbow Trout
Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression
Insulin-like growth factor binding protein 1 (IGFBP-1) is a hypoxia-inducible gene that plays an important role in regulating embryonic growth and development under hypoxic stress. The molecular mechanisms underlying hypoxia-induced IGFBP-1 gene expression in the embryonic tissues are not well understood. Here we report that the hypoxia-inducible factor 1 (HIF-1) pathway is established in early embryogenesis and mediates hypoxia-induced IGFBP-1 expression. Hypoxia increased the HIF-1 activity, and HIF-1α overexpression or CoCl(2) treatment resulted in elevated IGFBP-1 expression in zebra fish embryos. Although the zebra fish IGFBP-1 promoter contains 13 consensus hypoxia response elements (HREs), deletion and mutational analysis revealed that only the HRE positioned at â1090/â1086 is required for the hypoxia and HIF-1 induction. Further experiments revealed that there is an HIF-1 ancillary sequence (HAS) adjacent only to the functional HRE. Mutation of this HAS greatly reduced the responsiveness of the IGFBP-1 promoter to hypoxia and HIF-1. The HAS does not directly bind to HIF-1 or affect the binding of the HRE to HIF-1. The HAS is bound to a nuclear protein(s), and this HAS binding activity is reduced by hypoxia. These results suggest that HIF-1 mediates hypoxia-induced IGFBP-1 gene expression in early development by selectively interacting with the â1090/â1086 HRE and its adjacent HAS
Biosynthesis of 17α,20α-dihydroxy-4-pregnen-3-one from 17α-hydroxyprogesterone by Goldfish (Carassius auratus) Spermatozoa
Volume: 10Start Page: 381End Page: 38
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