Hoiamide A, a Sodium Channel Activator of Unusual Architecture from a Consortium of Two Papua New Guinea Cyanobacteria

Pereira, Alban R.; Cao, Zhengyu; Murray, Thomas F.; Gerwick, William H.

doi:10.1016/j.chembiol.2009.06.012

Cited by 86 publications

(80 citation statements)

References 56 publications

(67 reference statements)

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“…12) was purified as the active principle, causing a dose-dependent and rapid influx of [Na + ] in neocortical neurons. 167 Hoiamide A, however, produced a maximum Na + influx less than the full VGSC agonist batrachotoxin, suggesting that hoiamide A is a partial agonist. 167 The MOA of hoiamide A was interrogated using the VGSC inhibitor tetrodotoxin, NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX, monitoring for hoiamide A-induced elevation in [Na + ] in neocortical neurons.…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 87%

“…167 Hoiamide A, however, produced a maximum Na + influx less than the full VGSC agonist batrachotoxin, suggesting that hoiamide A is a partial agonist. 167 The MOA of hoiamide A was interrogated using the VGSC inhibitor tetrodotoxin, NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX, monitoring for hoiamide A-induced elevation in [Na + ] in neocortical neurons. 167 Tetrodotoxin A and MK-801, but not NBQX, caused a significant decrease in hoiamide A-induced Na + influx and an increase in maximum response of Na + influx with pyrethroid and brevetoxin 3 cotreatment.…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 87%

“…167–169 Using a bioactivity-directed approach, hoiamide A (Fig. 12) was purified as the active principle, causing a dose-dependent and rapid influx of [Na + ] in neocortical neurons.…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 99%

“…167 The MOA of hoiamide A was interrogated using the VGSC inhibitor tetrodotoxin, NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX, monitoring for hoiamide A-induced elevation in [Na + ] in neocortical neurons. 167 Tetrodotoxin A and MK-801, but not NBQX, caused a significant decrease in hoiamide A-induced Na + influx and an increase in maximum response of Na + influx with pyrethroid and brevetoxin 3 cotreatment. 167 This indicated a positive allosteric interaction between the hoiamide A binding site and neurotoxin sites 5 and 7, and suggested that hoiamide A occupies neurotoxin site 2.…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 99%

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Biological targets and mechanisms of action of natural products from marine cyanobacteria

2015

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Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial.

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Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 87%

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 87%

“…167–169 Using a bioactivity-directed approach, hoiamide A (Fig. 12) was purified as the active principle, causing a dose-dependent and rapid influx of [Na + ] in neocortical neurons.…”

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 99%

Section: Mechanisms Of Action and Direct Cellular Targets Of Biologmentioning

confidence: 99%

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Biological targets and mechanisms of action of natural products from marine cyanobacteria

2015

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“…The alkaloidal steroid batrachotoxin (BTX) is found in frog, bird, and insect species and has served as a primary tool for determining site 2 functional roles in Na V channels [207]. Antillatoxin and hoiamide are two structurally unique Na V agonists isolated from marine cyanobacteria [208,209]. Both molecules were found to partially displace [ Site 2 toxins share the characteristic of preferential binding to open-state Na V channels and are able to modulate several functional Na V properties.…”

Section: Sitementioning

confidence: 99%

Discovery and characterization of NaV modulatory venom peptides

Wingerd¹

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Voltage-gated sodium channels (Na V ) are integral membrane proteins that are responsible for the increase in sodium permeability that initiates and propagates the rising phase of action potentials, carrying electrical signals along nerve fibers and through excitable cells. Na V channels play a diverse role in neurophysiology and neurotransmission, as well as serving as molecular targets for several groups of neurotoxins that bind to different receptor sites and alter voltage-dependent activation, inactivation and conductance. There are nine Na V channel isoforms so far discovered, each of which display distinct functional profiles and tissue-specific expression patterns. The modulation of specific isoforms for therapeutic purposes has become an important research objective for the treatment of conductance diseases exhibiting phenotypes of chronic pain, epilepsy, myotonia, seizure, and cardiac arrhythmia. However, because of the high sequence similarity and structural homology between Na V channel isoforms, many current therapeutics that target Na V channels -the vast majority of which are small molecules -lack specificity between isoforms, or even other voltage-gated ion channels. The current push for greater selectivity while maintaining a relevant degree of potency has led the focus away from small molecules and towards the discovery and development of peptidic ligands for therapeutic use. Venom derived peptides have proven to be naturally potent and selective bioactive molecules, exhibiting inherent secondary structures that add stability through the formation of disulfide bonds. Organisms such as cone snails and spiders have evolved venom for the purpose of prey capture and defense, therefore many of the components exhibit paralytic qualities and specifically target Na V channels. Much of the discovery process has focused on screening crude venoms for a particular function and then isolating the molecule responsible for that function using assay guided purification.The first section of this thesis describes the development of a cell-based, high-throughput functional assay for the detection of Na V modulating venom peptides in crude venom. This assay was successfully implemented and resulted in the isolation and sequencing of MVIA from Conus magus. Initial results and sequence similarity placed MVIA into the δ-conotoxin family, a poorly described class of peptides that inhibits fast inactivation. However, multiple solid-phase synthesis and bacterial recombinant expression methods were unsuccessful in producing enough of the extremely hydrophobic δ-MVIA for further characterization. As no more C. magus crude venom was available, this project was left until optimized methods of production for highly hydrophobic peptides could be developed.ii An optimized method of bacterial recombinant expression was successful in producing large yields of another venom peptide, β/δ-TRTX-Pre1a, isolated from the spider Psalmopoeus reduncus. The same recombinant expression method was also used to produce uniformly label...

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Eubacteria – 2

Kornprobst

2014

Encyclopedia of Marine Natural Products

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Hoiamide A, a Sodium Channel Activator of Unusual Architecture from a Consortium of Two Papua New Guinea Cyanobacteria

Cited by 86 publications

References 56 publications

Biological targets and mechanisms of action of natural products from marine cyanobacteria

Biological targets and mechanisms of action of natural products from marine cyanobacteria

Discovery and characterization of NaV modulatory venom peptides

Eubacteria – 2

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