Publications by authors named "Nicholas J Palmer"

4 Publications

  • Page 1 of 1

Non-Equilibrium Mass Exchange in AOT Reverse Micelles.

J Phys Chem B 2020 01 18;124(1):144-148. Epub 2019 Dec 18.

Departments of Pharmacology, Biochemistry and Biophysics, and Medicine , University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.

Reverse micelles (RMs) composed of water and sodium bis(2-ethylhexyl)sulfosuccinate (AOT) in isooctane have a remarkably narrow size distribution around a mean value determined by the water loading ratio of the system. It has been proposed that RMs establish this equilibrium size distribution either by the diffusion of individual components through the isooctane phase or by cycles of fusion and fission. To examine these mechanisms, a 24 μs all-atom molecular dynamics simulation of a system containing one small RM and one large RM was performed. Results show that the net movement of water from the small RM to the large RM occurred in a direction that made the small RM smaller and the large RM larger-according to water loading ratios that would have been appropriate for their size. Changes in AOT number that would bring the water loading ratio of each RM closer to that of the overall system only occurred via cycles of RM fusion and fission. These behaviors are most likely driven by the electrostatics of sodium AOT and the dielectric effects of water.
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http://dx.doi.org/10.1021/acs.jpcb.9b08511DOI Listing
January 2020

Identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.

ACS Med Chem Lett 2013 Jul 8;4(7):585-9. Epub 2013 May 8.

Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, University of Leuven , Leuven, Belgium.

Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition.
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http://dx.doi.org/10.1021/ml400095mDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030314PMC
July 2013

A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIβ.

Antimicrob Agents Chemother 2013 Oct 29;57(10):4971-81. Epub 2013 Jul 29.

Department of Infectious Diseases and Immunology, Virology Division, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.

Despite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in an in vitro kinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model.
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http://dx.doi.org/10.1128/AAC.01175-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811463PMC
October 2013

Stereoselective synthesis of N-alkylaziridines from N-chloroamines.

Chem Commun (Camb) 2006 Nov 5(41):4338-40. Epub 2006 Sep 5.

School of Chemical Sciences & Pharmacy, UEA, Norwich, UK NR4 7TJ.

We report the first racemic and stereoselective synthesis of cis- and trans-N-alkylaziridines viaN-chloroamines; using this methodology an N-3,4,5-trimethoxybenzylaziridine was synthesised and efficiently cleaved, affording the corresponding NH aziridine in high yield.
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http://dx.doi.org/10.1039/b608504kDOI Listing
November 2006