The consequences of genetic and pharmacologic reduction in sphingolipid synthesis

Schiffmann, Raphael

doi:10.1007/s10545-014-9758-8

Cited by 8 publications

(4 citation statements)

References 89 publications

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“…The current challenge is to avoid lethal implication of sphingolipid synthesis blockade, which largely depends on the magnitude (i.e. global and non‐global blockade), the target within the pathway and appropriate intracellular or extracellular inhibition as per the desired outcome (Schiffmann, 2015; Schwalm et al, 2014). Partial inhibition is generally benign, as demonstrated in preclinical models (Schiffmann, 2015).…”

Section: Special Considerations For Cardiorenal Syndromementioning

confidence: 99%

“…global and non‐global blockade), the target within the pathway and appropriate intracellular or extracellular inhibition as per the desired outcome (Schiffmann, 2015; Schwalm et al, 2014). Partial inhibition is generally benign, as demonstrated in preclinical models (Schiffmann, 2015). Targeting Des‐1 is largely contemplated to restore dihydroceramide and ceramide balance.…”

Section: Special Considerations For Cardiorenal Syndromementioning

confidence: 99%

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Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

Savira

Magaye

Liew

et al. 2020

British J Pharmacology

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Cardiorenal syndrome (CRS) is a multi-organ disease, encompassing heart, kidney and vascular system dysfunction. CRS is a worldwide problem, with high morbidity, mortality, and inflicts a significant burden on the health care system. The pathophysiology is complex, involving interactions between neurohormones, inflammatory processes, oxidative stress and metabolic derangements. Therapies remain inadequate, mainly comprising symptomatic care with minimal prospect of full recovery. Challenges include limiting the contradictory effects of multi-organ targeted drug prescriptions and continuous monitoring of volume overload. Novel strategies such as multi-organ transplantation and innovative dialysis modalities have been considered but lack evidence in the CRS context. The adjunct use of pharmaceuticals targeting alternative pathways showing positive results in preclinical models also warrants further validation in the clinic. In recent years, studies have identified the involvement of gut dysbiosis, uraemic toxin accumulation, sphingolipid imbalance and other unconventional contributors, which has encouraged a shift in the paradigm of CRS therapy.

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Section: Special Considerations For Cardiorenal Syndromementioning

confidence: 99%

Section: Special Considerations For Cardiorenal Syndromementioning

confidence: 99%

Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

Savira

Magaye

Liew

et al. 2020

British J Pharmacology

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“…3b) where there is precedence in IEMs (e.g. Miglustat for the treatment of Gaucher disease (Platt and Jeyakumar 2008)) to reduce the consequence of toxic metabolite accumulation due to defective enzymes (Schiffmann 2015). We anticipate that progress in the structural biology of GYS and GYG (Chaikuad et al 2011; Zeqiraj et al 2014) should pave the next step forward in developing novel inhibitors for these enzymes.…”

Section: Multiple Intervention Avenues Within a Metabolic Pathwaymentioning

confidence: 99%

From structural biology to designing therapy for inborn errors of metabolism

Yue

2016

J of Inher Metab Disea

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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, citing examples of work from my group, collaborators and co-workers that cover diverse pathways of transsulfuration, cobalamin and glycogen metabolism. Taking into consideration that many inborn errors of metabolism result in the loss of enzyme function, this presentation aims to outline three key principles that guide the design of small molecule therapy in this technically challenging field: (1) integrating structural, biochemical and cell-based data to evaluate the wide spectrum of mutation-driven enzyme defects in stability, catalysis and protein-protein interaction; (2) studying multi-domain proteins and multi-protein complexes as examples from nature, to learn how enzymes are activated by small molecules; (3) surveying different regions of the enzyme, away from its active site, that can be targeted for the design of allosteric activators and inhibitors.

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“…To maximize intervention possibilities, there is rationale to survey the various steps surrounding the defective enzyme in a metabolic pathway, in search for possible therapeutic targets. Pertinent to this, the concept of substrate reduction therapy (SRT) has recently gained wide interest [12]. Rather than directly correcting the enzyme defect, SRT aims to attenuate the bioavailability of the compound that cannot be fully metabolized by the defective enzyme ('substrate reduction'), thereby restoring a steady-state balance of the pathway to lower the burden of the accumulating substrate.…”

Section: Introductionmentioning

confidence: 99%

Substrate reduction therapy for inborn errors of metabolism

Yue

Mackinnon

Bezerra

2019

Emerging Topics in Life Sciences

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Inborn errors of metabolism (IEM) represent a growing group of monogenic disorders each associated with inherited defects in a metabolic enzyme or regulatory protein, leading to biochemical abnormalities arising from a metabolic block. Despite the well-established genetic linkage, pathophysiology and clinical manifestations for many IEMs, there remains a lack of transformative therapy. The available treatment and management options for a few IEMs are often ineffective or expensive, incurring a significant burden to individual, family, and society. The lack of IEM therapies, in large part, relates to the conceptual challenge that IEMs are loss-of-function defects arising from the defective enzyme, rendering pharmacologic rescue difficult. An emerging approach that holds promise and is the subject of a flurry of pre-/clinical applications, is substrate reduction therapy (SRT). SRT addresses a common IEM phenotype associated with toxic accumulation of substrate from the defective enzyme, by inhibiting the formation of the substrate instead of directly repairing the defective enzyme. This minireview will summarize recent highlights towards the development of emerging SRT, with focussed attention towards repurposing of currently approved drugs, approaches to validate novel targets and screen for hit molecules, as well as emerging advances in gene silencing as a therapeutic modality.

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The consequences of genetic and pharmacologic reduction in sphingolipid synthesis

Cited by 8 publications

References 89 publications

Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

Cardiorenal syndrome: Multi‐organ dysfunction involving the heart, kidney and vasculature

From structural biology to designing therapy for inborn errors of metabolism

Substrate reduction therapy for inborn errors of metabolism

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