Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions

Burslem, George M.; Kyle, Hannah F.; Nelson, Adam; Edwards, Thomas A.; Wilson, Andrew J.

doi:10.1039/c7sc00388a

Cited by 33 publications

(33 citation statements)

References 133 publications

(125 reference statements)

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“…Once together, additional coactivators will interact with the HIF-1 complex to further regulate the transcription of target genes. Stabilization of the HIF-α subunit can occur in an oxygen-dependent (post-translational) and/or oxygen-independent (transcriptional) manner [ 10 ]. When oxygen is readily available, the HIF-α subunit is hydroxylated by prolyl-hydroxylases (PHDs), then polyubiquitinated by von Hippel–Lindau tumor suppressor protein (VHL) targeting it for proteasomal degradation [ 8 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

Morris

Agrawal

et al. 2020

Viruses

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Metabolic reprogramming of host cells is key to the foundation of a successful viral infection. Hypoxia inducible factors (HIFs) mediate oxygen utilization by regulating cellular metabolism and redox homeostasis. Under normoxic conditions, HIF proteins are synthesized and subsequently degraded following ubiquitination to allow for normal metabolic activities. Recent studies suggest that respiratory syncytial virus (RSV) has the ability to induce HIF-1α stabilization and accumulation through non-hypoxic mechanisms. This makes the HIF pathway a potential avenue of approach for RSV therapeutic development. Using a model of primary human small alveolar epithelial cells, we demonstrate RSV infections to greatly alter cellular metabolism in favor of the glycolytic and pentose phosphate pathways. Additionally, we show RSV infections to stabilize HIF-1α and HIF-2α expression in these cells. Inhibition of HIF-1α, but not HIF-2α, was found to significantly reduce RSV replication as well as the glycolytic pathway, as measured by the expression of hexokinase II. Our study contributes to the understanding of RSV-mediated changes to cellular metabolism and supports further investigation into anti-HIF-1α therapeutics for RSV infections.

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Section: Introductionmentioning

confidence: 99%

HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

Morris

Agrawal

et al. 2020

Viruses

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“…The HIF-1a/p300 PPI plays ak ey role in tumourm etabolism and thus represents ap romising anticancer target. [55,56] HIF-1a is at ranscription factor that regulates cellular responset oh ypoxia. When oxygen levels in the tissue are normal,H IF-1a is degraded rapidly.…”

Section: Resultsmentioning

confidence: 99%

“…[59,60] The large interaction surfacea rea comprising three helical regionso verw hich binding free energy is dispersed render the HIF-1a/p300 interaction challenging for inhibitor identification and design. [55] Epidithioketopiperazine containing molecules such as Chetomin [61] have been reported as HIF-1a/p300 inhibitor molecules, [62] however zinc ejection from p300, [63] has been shown to contribute to the molecular mode of action,w hich may lead to nonspecific effects. Several small-molecules have been identified as potentialH IF-1a inhibitors whilst ar ange of constrained peptidea nd helix mimetic inhibitors have also been described.…”

Section: Resultsmentioning

confidence: 99%

“…In this work, we apply dibromomaleimide stapling to the development of constrained peptide inhibitors of the HIF-1a/ p300 interaction-a promising but challenging target for anticancer drug-development. [55,56] Using ac ombination of fluorescence anisotropy competition assays, experimentalc ircular dichroism and molecular dynamics simulations, we show that when suitably positioned, introductiono ft he S,S-maleimide crosslinkw ithin a1 4r esidue sequence from the C-terminal region of HIF-1a (residues 812-826) does not lead to as ignificant increase in helicity of the unboundpeptide, yetthis modification does increasei nhibitory potency.T he effect can be rationalised using molecular dynamics simulations and difference circulard ichroism (CD) spectroscopy,w hich show that introductiono ft he constraint in the HIF-1a peptidel eads to better maintenance of the bioactivec onformation when bound to p300. The resultsh ighlight the importance of considering the conformational stabilityo ft he bound state in designing constrainedp eptides as inhibitors of PPIs.…”

Section: Introductionmentioning

confidence: 96%

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Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

Hetherington

Hegedűs

Edwards

et al. 2020

Chemistry A European J

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Protein–protein interactions (PPIs) control virtually all cellular processes and have thus emerged as potential targets for development of molecular therapeutics. Peptide‐based inhibitors of PPIs are attractive given that they offer recognition potency and selectivity features that are ideal for function, yet, they do not predominantly populate the bioactive conformation, frequently suffer from poor cellular uptake and are easily degraded, for example, by proteases. The constraint of peptides in a bioactive conformation has emerged as a promising strategy to mitigate against these liabilities. In this work, using peptides derived from hypoxia‐inducible factor 1 (HIF‐1α) together with dibromomaleimide stapling, we identify constrained peptide inhibitors of the HIF‐1α/p300 interaction that are more potent than their unconstrained sequences. Contrary to expectation, the increased potency does not correlate with an increased population of an α‐helical conformation in the unbound state as demonstrated by experimental circular dichroism analysis. Rather, the ability of the peptide to adopt a bioactive α‐helical conformation in the p300 bound state is better supported in the constrained variant as demonstrated by molecular dynamics simulations and circular dichroism difference spectra.

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“…Cellular adaptation to hypoxia is largely regulated by a heterodimeric transcription factor, hypoxia-inducible factor (HIF), which consists of two sub-units; α and β. Whereas the β sub-unit is relatively insensitive to alteration in oxygen levels, the level of the alpha sub-unit (HIF-α) is highly dependent on cellular oxygen tension [ 11 , 12 ]. HIF-α has two major isoforms; HIF-1α, HIF-2α and one additional minor isoform HIF-3α [ 11 , 13 ].…”

Section: Role Of Hypoxia and Hypoxia-inducible Factor (Hif)mentioning

confidence: 99%

Ischaemia reperfusion injury: mechanisms of progression to chronic graft dysfunction

Situmorang

Sheerin

2018

Pediatr Nephrol

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The increasing use of extended criteria organs to meet the demand for kidney transplantation raises an important question of how the severity of early ischaemic injury influences long-term outcomes. Significant acute ischaemic kidney injury is associated with delayed graft function, increased immune-associated events and, ultimately, earlier deterioration of graft function. A comprehensive understanding of immediate molecular events that ensue post-ischaemia and their potential long-term consequences are key to the discovery of novel therapeutic targets. Acute ischaemic injury primarily affects tubular structure and function. Depending on the severity and persistence of the insult, this may resolve completely, leading to restoration of normal function, or be sustained, resulting in persistent renal impairment and progressive functional loss. Long-term effects of acute renal ischaemia are mediated by several mechanisms including hypoxia, HIF-1 activation, endothelial dysfunction leading to vascular rarefaction, sustained pro-inflammatory stimuli involving innate and adaptive immune responses, failure of tubular cells to recover and epigenetic changes. This review describes the biological relevance and interaction of these mechanisms based on currently available evidence.

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Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions

Abstract: The state of the art in identifying protein–protein interaction inhibitors of hypoxia inducible factor – a promising target for anticancer drug design – is described.

Cited by 33 publications

References 133 publications

HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

HIF-1α Modulates Core Metabolism and Virus Replication in Primary Airway Epithelial Cells Infected with Respiratory Syncytial Virus

Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

Ischaemia reperfusion injury: mechanisms of progression to chronic graft dysfunction

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