Optimisation of Conoidin A, a Peroxiredoxin Inhibitor

Gu, Lin; Botting, CatherineâH.; Evans, KathrynâM.; Walton, JeffreyâA.âG.; Xu, Guogang; Slawin, Alexandra M. Z.; Westwood, NicholasâJ.

doi:10.1002/cmdc.200900391

Cited by 27 publications

(20 citation statements)

References 30 publications

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“…Since these hyperoxidation and alkylation mechanisms can occur simultaneously, their effects on enzyme activity are expected to be additive. This is supported by the reduced inhibitory activity of a deoxygenated conoidin A derivative against TgPrxII (Liu, et al, 2010). …”

Section: Discussionmentioning

confidence: 84%

“…A cell permeable organic compound, 2,3-bis(bromomethyl)quinoxaline-1,4-dioxide (conoidin A), has been shown to inhibit the hyperoxidation activity of peroxiredoxin II from the apicomplexan parasite Toxoplasma gondii (TgPrxII), as well as human peroxiredoxins I and II (Haraldsen, et al, 2009). Conoidin A inhibits TgPrxII with an IC 50 of 23 μM by binding covalently to the peroxidatic cysteine (Liu, et al, 2010). More relevant to the present study, conoidin A treatment of A. ceylanicum eggs purified from the feces of infected hamsters as well as eggs from field isolates of human hookworms resulted in a significant inhibition of egg hatching, revealing the nematicidal activity of conoidin A (Treger, et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Peroxiredoxin-1 from the Human Hookworm Ancylostoma ceylanicum Forms a Stable Oxidized Decamer and Is Covalently Inhibited by Conoidin A

Nguyen

Pool

Wong

et al. 2013

Chemistry & Biology

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Summary Hookworms are parasitic nematodes that have a devastating impact on global health, particularly in developing countries. We report a biochemical and structural analysis of a peroxiredoxin from the hookworm Ancylostoma ceylanicum, AcePrx-1. Peroxiredoxins provide antioxidant protection and act as signaling molecules and chaperones. AcePrx-1 is expressed in adult hookworms and can be inactivated by 2,3-bis(bromomethyl)quinoxaline-1,4-dioxide (conoidin A). Conoidin A inactivates AcePrx-1 by alkylating or crosslinking the catalytic cysteines, while maintaining the enzyme in the “locally unfolded” conformation. Irreversible oxidation of the resolving cysteine may contribute additional inhibitory activity. A crystal structure of oxidized AcePrx-1 reveals a disulfide-linked decamer. A helix macrodipole near the active site increases the reactivity of the catalytic cysteines to conoidin A. This work demonstrates the promise of conoidin compounds as probes to evaluate peroxiredoxins as drug targets in human parasites.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Peroxiredoxin-1 from the Human Hookworm Ancylostoma ceylanicum Forms a Stable Oxidized Decamer and Is Covalently Inhibited by Conoidin A

Nguyen

Pool

Wong

et al. 2013

Chemistry & Biology

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“…Conoidin A, a specific Prx activity inhibitor, is currently under evaluation [32]. Tavender and Bulleid found Prx4 oxidation to be indicative of the degree of oxidative stress in the ER [3].…”

Section: Discussionmentioning

confidence: 99%

Peroxiredoxin 4: a multifunctional biomarker worthy of further exploration

Schulte

2011

BMC Med

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Currently, there is much interest in identifying clinically relevant biomarkers, as they have the potential to be high utility non-invasive tools for early diagnosis and reliable patient monitoring in numerous conditions. Since its discovery almost 15 years ago, research on the ubiquitous antioxidant enzyme peroxiredoxin 4 (Prx4) has culminated in the recognition that Prx4 levels are different in blood drawn from the healthy general population and patients with acute or chronic diseases. In this commentary, the most striking research data from different in vitro approaches, animal models and human observational studies are discussed collectively, highlighting the clinical importance of Prx4 as a multifunctional staging and prognosis biomarker. In this context, the oxidative state of patients may be reflected by intra- and extracellular Prx4 levels, redox state, oligomerization and nitro-oxidative modifications of the enzyme. A consolidated model of the potential role and origin of circulating Prx4 is presented to stimulate further investigations in light of the current biomarker situation.

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“…Whilst the use of a TgPrxII knock-out parasites suggested that this was not the relevant target, studies with the purified protein confirmed that Conoidin A was a novel inhibitor of this enzyme. Further studies on the mode of inhibition of TgPrxII by Conoidin A and some novel analogues have also been reported by us recently (G. Liu et al, 2010). Our collaborative team has also focused on the use of the yeast-3-hybrid system for the identification of potential protein targets of small molecules (Walton et al, 2009).…”

Section: Chemical Geneticsmentioning

confidence: 68%