3-Normeridamycin: A Potent Non-Immunosuppressive Immunophilin Ligand is Neuroprotective in Dopaminergic Neurons

Summers, Mia Y.; Leighton, Margaret; Liu, Danni; Pong, Kevin; Graziani, Edmund I.

doi:10.1038/ja.2006.26

Cited by 19 publications

(9 citation statements)

References 22 publications

(19 reference statements)

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“…immunophilin ͉ L-type voltage-gated calcium channel ͉ natural products ͉ neurodegeneration ͉ stroke I mmunophilin ligands, such as FK506, cyclosporin A, rapamycin, 3-normeridamycin, V-10,367, and GPI-1046, have been shown to have neuroprotective activities (1)(2)(3)(4). Immunophilins comprise the family of FK506-binding proteins (FKBPs) having peptidyl-prolyl cis-trans isomerase (PPIase) activities and were proposed as likely targets for mediating this neurotrophic activity, although there is disagreement as to their specific mechanism (5-7).…”

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confidence: 99%

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Ruan

Pong

Jow

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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109

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Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the ␤1-subunit of L-type voltage-dependent Ca 2؉ channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca 2؉ channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca 2؉ -induced cell death by modulating Ca 2؉ channels and promote neurite outgrowth via FKBP52 binding.immunophilin ͉ L-type voltage-gated calcium channel ͉ natural products ͉ neurodegeneration ͉ stroke

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confidence: 99%

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Ruan

Pong

Jow

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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109

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“…Meridamycin (1) and its naturally occurring analogue 3-normeridamycin (2) are nonimmunosuppressive, FKBP12-binding macrocyclic polyketides with potent neuroprotective activity in dopaminergic neurons. 17 Efforts to develop 1 into a clinically useful neuroprotective agent proved challenging, mainly due to the difficulty to further improve its production in the native producing strain after reaching a certain level through a traditional medium optimization and strain improvement process. This presents a big hurdle to chemically derivatize 1 for superior analogues, which requires exponentially greater quantities of material.…”

Section: Resultsmentioning

confidence: 99%

Rapid Cloning and Heterologous Expression of the Meridamycin Biosynthetic Gene Cluster Using a Versatile Escherichia coli−Streptomyces Artificial Chromosome Vector, pSBAC

et al. 2009

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Expression of biosynthetic pathways in heterologous hosts is an emerging approach to expedite production improvement and biosynthetic modification of natural products derived from microbial secondary metabolites. Herein we describe the development of a versatile Escherichia coli-Streptomyces shuttle Bacterial Artificial Chromosomal (BAC) conjugation vector, pSBAC, to facilitate the cloning, genetic manipulation, and heterologous expression of actinomycetes secondary metabolite biosynthetic gene clusters. The utility of pSBAC was demonstrated through the rapid cloning and heterologous expression of one of the largest polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) biosynthetic pathways: the meridamycin biosynthesis gene cluster (mer). The entire mer gene cluster ( approximately 90 kb) was captured in a single pSBAC clone through a straightforward restriction enzyme digestion and cloning approach and transferred into Streptomyces lividans. The production of meridamycin (1) in the heterologous host was achieved after replacement of the original promoter with an ermE* promoter and was enhanced by feeding with a biosynthetic precursor. The success of heterologous expression of such a giant gene cluster demonstrates the versatility of BAC cloning technology and paves the road for future exploration of expression of the meridamycin biosynthetic pathway in various hosts, including strains that have been optimized for polyketide production.

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“…13) [34]. At the time the project began, it was known that certain macrocyclic immunophilins like FK-506, meridamycin, and normeridamycin displayed neuroprotective activity in animal models of stroke [35,36]. More interestingly, the compounds stimulated neuronal outgrowth in culture.…”

Section: Immunophilins For Stroke -Ils-920mentioning

confidence: 99%

Targeting neurodegenerative diseases: Drug discovery in a challenging arena

Abou‐Gharbia

Childers

2012

Pure and Applied Chemistry

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Neurodegenerative diseases represent one of the health care community's truly unmet medical needs. They can be loosely classified into two categories, acute and chronic. One of the best known chronic neurodegenerative diseases, Alzheimer's disease, represents a serious health care problem that may well exceed the limits of current fiscal and care giver resources. No disease-modifying therapeutic agents have been identified, and the few available symptomatic treatments possess limitations in their duration of action and side effects. Despite decades of drug discovery research and numerous clinical trials, no truly effective treatment for stroke, the most prevalent acute neurodegenerative disease, has been identified. This article summarizes two recent drug discovery projects, one targeting Alzheimer's disease and the other targeting ischemic stroke. Both projects involved design, synthesis, and biological evaluation of a novel series of heterocyclic derivatives.According to the National Institute of Neurological Disorders and Stroke, there are over 600 diseases known to afflict the nervous system. Among these are a large group of afflictions that can be generally classified as neurodegenerative diseases. Neurodegenerative diseases, as the name suggests, are characterized by progressive dysfunction of the nervous system. They can be further subdivided into two general categories. Chronic neurodegenerative diseases are characterized by a slow, progressive loss of neuronal function. The etiologies of chronic neurodegenerative diseases are numerous (see Saxena and Caroni [1] for recent references), and many are still poorly understood. Chronic neurodegenerative diseases were once thought to be exclusively hereditary in nature. However, the discovery of acquired chronic conditions such as Creutzfeld-Jacob disease and bovine spongiform encephalopathy (mad cow disease) has dispelled that generalization. The second category includes acute conditions like stroke, traumatic brain injury, and ischemic hypoxia such as that seen in myocardial infarction and prolonged cardiac surgery. These were once thought to be simply injury-related conditions rather than neurodegenerative disorders, but subsequent research has shown that all of these conditions have components of progressive neurodegeneration that can occur over a period of weeks to months. Taken together, neuro degenerative diseases are one of the major causes of death today.

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3-Normeridamycin: A Potent Non-Immunosuppressive Immunophilin Ligand is Neuroprotective in Dopaminergic Neurons

Cited by 19 publications

References 22 publications

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities

Rapid Cloning and Heterologous Expression of the Meridamycin Biosynthetic Gene Cluster Using a Versatile Escherichia coli−Streptomyces Artificial Chromosome Vector, pSBAC

Targeting neurodegenerative diseases: Drug discovery in a challenging arena

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