2016
DOI: 10.1007/s10545-016-9923-3
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From structural biology to designing therapy for inborn errors of metabolism

Abstract: At the SSIEM Symposium in Istanbul 2010, I presented an overview of protein structural approaches in the study of inborn errors of metabolism (Yue and Oppermann 2011). Five years on, the field is going strong with new protein structures, uncovered catalytic functions and novel chemical matters for metabolic enzymes, setting the stage for the next generation of drug discovery. This article aims to update on recent advances and lessons learnt on inborn errors of metabolism via the protein-centric approach, citin… Show more

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Cited by 14 publications
(14 citation statements)
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“…LOF variants of proteins are generally little studied, and their activation poses bigger challenge that inhibition of a given activity. Nevertheless, several approaches have been investigated with some success [16]. One of the approaches was the development of so-called pharmaceutical chaperones [12], but to the best of our knowledge activation of natural protein chaperones as a way of stabilizing LOF enzymes has not been widely tested and such effect was never proved by means of structural biology.…”
Section: Discussionmentioning
confidence: 99%
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“…LOF variants of proteins are generally little studied, and their activation poses bigger challenge that inhibition of a given activity. Nevertheless, several approaches have been investigated with some success [16]. One of the approaches was the development of so-called pharmaceutical chaperones [12], but to the best of our knowledge activation of natural protein chaperones as a way of stabilizing LOF enzymes has not been widely tested and such effect was never proved by means of structural biology.…”
Section: Discussionmentioning
confidence: 99%
“…In fact, such small molecular agents referred to as pharmaceutical chaperones [11] have been investigated for a number of targets related to protein misfolding [12,13] resulting in several drug candidates and approved drugs [14]. Yet, the development of such a stabilizing agent is usually a tedious project [11][12][13]15] and the utmost importance of structural biology was underlined in such investigations [16].…”
mentioning
confidence: 99%
“…Several PCs against lysosomal disorders are already in clinical trials demonstrating a promising approach toward small molecule-based therapies [119,120]. These therapeutics may be classified as active site-specific PCs, and nonactive site PCs [121]. The initially described PCs rather belonged to the first type, which were developed through derivatization of natural ligands and agonists [117,121], largely based on the realization that supplementation with cofactor and coenzymes increases the activity and stability of numerous variant enzymes [122].…”
Section: Pcsmentioning
confidence: 99%
“…These therapeutics may be classified as active site-specific PCs, and nonactive site PCs [121]. The initially described PCs rather belonged to the first type, which were developed through derivatization of natural ligands and agonists [117,121], largely based on the realization that supplementation with cofactor and coenzymes increases the activity and stability of numerous variant enzymes [122]. Indeed, a chaperone response on mutant PAH seems to be an important molecular mechanism behind BH4-responsive PKU [123].…”
Section: Pcsmentioning
confidence: 99%
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