Targeting FKBP isoforms with small-molecule ligands

Blackburn, Elizabeth A.; Walkinshaw, Malcolm D.

doi:10.1016/j.coph.2011.04.007

Cited by 66 publications

(75 citation statements)

References 45 publications

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“…A focus on FKBP inhibitors as drug candidates has additional advantages. FKBPs have been well studied for their pharmacological interest, several sequences have been identified, and three-dimensional structures from X-ray and NMR studies are available; therefore, screening strategies for the discovery of new drug candidates have been established [363].…”

Section: Discussionmentioning

confidence: 99%

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Sulistio

Heese

2015

Mol Neurobiol

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One of the shared hallmarks of neurodegenerative diseases is the accumulation of misfolded proteins. Therefore, it is suspected that normal proteostasis is crucial for neuronal survival in the brain and that the malfunction of this mechanism may be the underlying cause of neurodegenerative diseases. The accumulation of amyloid plaques (APs) composed of amyloid-beta peptide (Aβ) aggregates and neurofibrillary tangles (NFTs) composed of misfolded Tau proteins are the defining pathological markers of Alzheimer's disease (AD). The accumulation of these proteins indicates a faulty protein quality control in the AD brain. An impaired ubiquitin-proteasome system (UPS) could lead to negative consequences for protein regulation, including loss of function. Another pivotal mechanism for the prevention of misfolded protein accumulation is the utilization of molecular chaperones. Molecular chaperones, such as heat shock proteins (HSPs) and FK506-binding proteins (FKBPs), are highly involved in protein regulation to ensure proper folding and normal function. In this review, we elaborate on the molecular basis of AD pathophysiology using recent data, with a particular focus on the role of the UPS and molecular chaperones as the defensive mechanism against misfolded proteins that have prion-like properties. In addition, we propose a rational therapy approach based on this mechanism.

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Section: Discussionmentioning

confidence: 99%

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Sulistio

Heese

2015

Mol Neurobiol

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“…Importantly, structural details of target proteins and their corresponding mutant isoforms can also be applied to inform drug design strategies, as recently reviewed [319][320][321][322][323][324]. For example, detailed knowledge of a target protein's three-dimensional structure facilitates the development of more selective drugs [169,325,326] and second-generation therapeutics for treating patients with unresponsive disease [327]. In addition, comparative analysis of target protein structures of currently marketed drugs allows for efficient drug repurposing to accelerate drug development for treating rare and orphan diseases [328][329][330].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics and variability in drug response: a protein structural perspective

Lahti

Tang

Capriotti

et al. 2012

J. R. Soc. Interface.

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Marketed drugs frequently perform worse in clinical practice than in the clinical trials on which their approval is based. Many therapeutic compounds are ineffective for a large subpopulation of patients to whom they are prescribed; worse, a significant fraction of patients experience adverse effects more severe than anticipated. The unacceptable risk -benefit profile for many drugs mandates a paradigm shift towards personalized medicine. However, prior to adoption of patient-specific approaches, it is useful to understand the molecular details underlying variable drug response among diverse patient populations. Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms correlated with differential therapeutic outcomes. Together these advances provide the opportunity to examine how altered protein structures arising from genetic differences affect protein -drug interactions and, ultimately, drug response. In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions. Next, we describe the impact of coding mutations on protein structures and drug response. Finally, we highlight tools for analysing protein structures and protein -drug interactions and discuss their application for understanding altered drug responses associated with protein structural variants.

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“…Fourteen FKBP proteins are known [201], and a clarification of their role in the nervous system is still awaited. A systematic evaluation of binding potencies and affinity trends for FK506-related, small immunophilin ligands on FKBP proteins (including tau-relevant FKBP51 and FKBP52) is now available [203,204].…”

Section: Hsp90mentioning

confidence: 99%

“…Non-immunosuppressive, neuroprotective smaller ligands such as 2.62 (GPI-1046) [199] and its optimized analog V-10367 (2.63a) [200] mimic the FKBP-binding domain of FK506. Their neurotrophic activity is observed in clinical trials [201]. The neuroprotective action of pipecoline ketoamides 2.62 and 2.63a in vivo is likely mediated by larger FKBP52 immunophilins [202].…”

Section: Hsp90-co-chaperone Complexes: Direct Inhibitionmentioning

confidence: 99%

Targeting the Protein Quality Control (PQC) Machinery

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

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Targeting FKBP isoforms with small-molecule ligands

Cited by 66 publications

References 45 publications

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease

Bioinformatics and variability in drug response: a protein structural perspective

Targeting the Protein Quality Control (PQC) Machinery

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