Novel Drugs Targeting the c-Ring of the F&lt;sub&gt;1&lt;/sub&gt;F&lt;sub&gt;O&lt;/sub&gt;-ATP Synthase

Pagliarani, Alessandra; Nesci, Salvatore; Ventrella, Vittoria

doi:10.2174/1389557516666160211120955

Cited by 21 publications

(15 citation statements)

References 69 publications

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“…ATP synthase is also being used and recommended as an effective molecular drug target for multiple disease conditions and for the regulation of energy metabolism ([ 20 , 26 , 55 , 56 ] and references therein). Selective and specific inhibition makes ATP synthase an excellent molecular target for the development of new antimicrobial agents.…”

Section: Atp Synthase As a Molecular Drug Targetmentioning

confidence: 99%

A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase

Ahmad

Hassan²,

Azim

2017

CMC

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For centuries, phytochemicals have been used to prevent and cure multiple health ailments. Phytochemicals have been reported to have antioxidant, antidiabetic, antitussive, antiparasitic, anticancer, and antimicrobial properties. Generally, the therapeutic use of phy-tochemicals is based on tradition or word of mouth with few evidence-based studies. Moreo-ver, molecular level interactions or molecular targets for the majority of phytochemicals are unknown. In recent years, antibiotic resistance by microbes has become a major healthcare concern. As such, the use of phytochemicals with antimicrobial properties has become perti-nent. Natural compounds from plants, vegetables, herbs, and spices with strong antimicrobial properties present an excellent opportunity for preventing and combating antibiotic resistant microbial infections. ATP synthase is the fundamental means of cellular energy. Inhibition of ATP synthase may deprive cells of required energy leading to cell death, and a variety of die-tary phytochemicals are known to inhibit ATP synthase. Structural modifications of phyto-chemicals have been shown to increase the inhibitory potency and extent of inhibition. Site-directed mutagenic analysis has elucidated the binding site(s) for some phytochemicals on ATP synthase. Amino acid variations in and around the phytochemical binding sites can re-sult in selective binding and inhibition of microbial ATP synthase. In this review, the therapeu-tic connection between dietary phytochemicals and ATP synthase is summarized based on the inhibition of ATP synthase by dietary phytochemicals. Research suggests selective target-ing of ATP synthase is a valuable alternative molecular level approach to combat antibiotic resistant microbial infections.

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Section: Atp Synthase As a Molecular Drug Targetmentioning

confidence: 99%

A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase

Ahmad

Hassan²,

Azim

2017

CMC

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“…The demand for evidence-based phytochemicals in general and plant-based phenolic constituents in particular as alternative remedies has increased [7, 13, 16–20]. A large number of dietary phenolic compounds from a variety of sources have been shown to have potential antitumor or antimicrobial properties [21–25].…”

Section: Introductionmentioning

confidence: 99%

Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase

Amini

Liu

Ahmad

2017

International Journal of Biological Macromolecules

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The naturally occurring olive phenolics tyrosol, hydroxytyrosol, dihydroxyphenylglycol (DHPG), and oleuropein are known to have antioxidant, antitumor, and antibacterial properties. In the current study, we examined whether the antimicrobial properties of tyrosol, hydroxytyrosol, DHPG, and oleuropein were linked to the inhibition of bacterial ATP synthase. Tyrosol, hydroxytyrosol, DHPG, and oleuropein inhibited Escherichia coli wild-type and mutant membrane-bound F1Fo ATP synthase to variable degrees. The growth properties of wild-type, null, and mutant strains in presence of above olive phenolics were also abrogated to variable degrees on limiting glucose and succinate. Tyrosol and oleuropein synergistically inhibited the wild-type enzyme. Comparative wild-type and mutant F1Fo ATP synthase inhibitory profiles suggested that αArg-283 is an important residue and olive phenolics bind at the polyphenol binding pocket of ATP synthase. Growth patterns of wild-type, null, and mutant strains in the presence of tyrosol, hydroxytyrosol, DHPG, and oleuropein also hint at the possibility of additional molecular targets. Our results demonstrated that ATP synthase can be used as a molecular target and the antimicrobial properties of olive phenolics in general and tyrosol in particular can be linked to the binding and inhibition of bacterial ATP synthase.

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“…A virtual chemical screening identified several compounds that were able to bind to cyclophilin D with a K D of <100 nM (Park et al ., ). Synthetic compounds from the diarylquinoline and organotin families instead target the c‐ring of the F‐ATPase and strongly inhibit the enzyme (Pagliarani et al ., ). A member of these families, tributyltin, induces mitochondrial swelling, which has long been associated with the PT, but is CsA‐insensitive, at least according to some authors (see, e.g.…”

Section: Inner Membrane Ion Channelsmentioning

confidence: 97%

Pharmacological modulation of mitochondrial ion channels

Leanza

Checchetto

Biasutto

et al. 2019

British J Pharmacology

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The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria‐specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear‐cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage‐dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane‐located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large‐scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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Novel Drugs Targeting the c-Ring of the F<sub>1</sub>F<sub>O</sub>-ATP Synthase

Cited by 21 publications

References 69 publications

A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase

A Therapeutic Connection between Dietary Phytochemicals and ATP Synthase

Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase

Pharmacological modulation of mitochondrial ion channels

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