The location of amantadine hydrochloride and free base within phospholipid multilayers: a neutron and X-ray diffraction study

Duff, K.C.; Cudmore, A.J.; Bradshaw, Jeremy P.

doi:10.1016/0005-2736(93)90392-d

Cited by 33 publications

(23 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, the interaction of many hydrophobic cation is thought to be facilitated by the hydrophobic nature of the lining of the internal cavity thought to be present in many potassium channels [53]–[56]. Amantadine readily partitions into lipid bilayers [57]–[59] and consequently could access the channel pore from the cytoplasmic side, even when the compound is applied externally. The discovery that a mutation on the internal side of the selectivity filter affects amantadine block suggests that amantadine blocks Kcv from the intracellular side.…”

Section: Discussionmentioning

confidence: 99%

Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

et al. 2009

View full text Add to dashboard Cite

BackgroundUnderstanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs.Methodology/Principal FindingsWe used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the T→S mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding.Conclusions/SignificanceThe data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features.

show abstract

Section: Discussionmentioning

confidence: 99%

Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Amantadine behaves as a lysosomotropic substance that passes easily through the lysosome membrane and accumulates in it. It could lower the pH of lysosome thus inhibit the protease activities 15 . Amantadine can also block the assembly of influenza virus during viral replication.…”

Section: Drug Screenmentioning

confidence: 99%

“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”

Smieszek

Przychodzen

Polymeropoulos

2020

Preprint

View full text Add to dashboard Cite

SARS-coronavirus 2 is the causal agent of the COVID-19 outbreak. SARS-Cov-2 entry into a cell is dependent upon binding of the viral spike (S) protein to cellular receptor and on cleavage of the spike protein by the host cell proteases such as Cathepsin L and Cathepsin B. CTSL/B are crucial elements of lysosomal pathway and both enzymes are almost exclusively located in the lysosomes.CTSL disruption offers potential for CoVID-19 therapies. The mechanisms of disruption include: decreasing expression of CTSL, direct inhibition of CTSL activity and affecting the conditions of CTSL environment (increase pH in lysosomes).We have conducted a high throughput drug screen gene expression analysis to identify compounds that would downregulate the expression of CTSL/CTSB. One of the top significant results shown to downregulate the expression of the CTSL gene is Amantadine. Amantadine was approved by the US Food and Drug Administration in 1968 as a prophylactic agent for influenza and later for Parkinson's disease. It is available as a generic drug.. Amantadine in addition to downregulating CTSL appears to further disrupt lysosomal pathway , hence interfering with the capacity of the virus to replicate. It acts as a lysosomotropic agent altering the CTSL functional environment. We hypothesize that Amantadine could decrease the viral load in SARS-CoV-2 positive patients and as such it may serve as a potent therapeutic decreasing the replication and infectivity of the virus likely leading to better clinical outcomes. Clinical studies will be needed to examine the therapeutic utility of amantadine in COVID-19 infection.was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

show abstract

“…Studies undertaken so far suggest two possible sites of location of the drug in the lipid bilayer: in the polar phospholipid headgroup region and inside the hydrophobic center of the bilayer in the region of phospholipid hydrocarbon chains. 21 The present study was undertaken to distinguish between these two possible locations of amantadine in lipid bilayers. A new spin-labeled amantadine was synthesized in which the spin label moiety was attached to the amino group of amantadine through an amide bond.…”

Section: Introductionmentioning

confidence: 99%

Partitioning and Localization of Spin-Labeled Amantadine in Lipid Bilayers: An Epr Study

Subczynski¹,

Wojas²,

Pezeshk³

et al. 1998

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

EPR was used to study the distribution of the spin-labeled amantadine (AA-SL) between the bulk hydrophobic-hydrocarbon solvent, light paraffin oil, and water and between hydrophobic-hydrocarbon chain region of lipid membranes and water. The AA-SL molecules were soluble in both hydrophobic and polar regions of investigated systems. It was shown that the partition coefficient of AA-SL between the hydrocarbon region of the L-alpha-dimyristoylphosphatidylcholine fluid-phase membrane and water is much higher than between bulk hydrocarbon solvent and water. Furthermore, the partitioning of AA-SL into membranes of multilamellar liposomes made of L-alpha-dimyristoylphosphatidylcholine, L-alpha-dipalmitoylphosphatidylcholine, and L-alpha-distearoylphosphatidylcholine was studied as a function of temperature, indicating no abrupt change at the main phase transition of these membranes. It is also clear from our data that AA-SL can penetrate into the gel-phase membrane practically with the same partitioning as into the fluid-phase membrane. Furthermore, it was shown that at least part of the AA-SL molecule is deeply buried in the hydrocarbon chain region of the membrane.

show abstract

The location of amantadine hydrochloride and free base within phospholipid multilayers: a neutron and X-ray diffraction study

Cited by 33 publications

References 18 publications

Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

“Amantadine disrupts lysosomal gene expression; potential therapy for COVID19”

Partitioning and Localization of Spin-Labeled Amantadine in Lipid Bilayers: An Epr Study

Contact Info

Product

Resources

About