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Biomedical subjects

M G Finn

Publications and source records attributed to M G Finn.

At least 19 recordsLinked to original sources
PubMed2006

Global structural changes in hepatitis B virus capsids induced by the assembly effector HAP1.

Hepatitis B virus (HBV) is a leading cause of liver disease and hepatocellular carcinoma; over 400 million people are chronically infected with HBV. Specific anti-HBV treatments, like most antivirals, target enzymes that are similar to host proteins. Virus capsid protein has no human homolog, making its assembly a promising but undeveloped therapeutic target. HAP1 [methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate], a heteroaryldihydropyrimidine, is a potent HBV capsid assembly activator and misdirector. Knowledge of the structural basis for this activity would directly benefit the development of capsid-targeting therapeutic strategies. This report details the crystal structures of icosahedral HBV capsids with and without HAP1. We show that HAP1 leads to global structural changes by movements of subunits as connected rigid bodies. The observed movements cause the fivefold vertices to protrude from the liganded capsid, the threefold vertices to open, and the quasi-sixfold vertices to flatten, explaining the effects of HAP1 on assembled capsids and on the assembly process. We have identified a likely HAP1-binding site that bridges elements of secondary structure within a capsid-bound monomer, offering explanation for assembly activation. This site also interferes with interactions between capsid proteins, leading to quaternary changes and presumably assembly misdirection. These results demonstrate the plasticity of HBV capsids and the molecular basis for a tenable antiviral strategy.

Antiviral Agents↗
PubMed2006

Incorporation of 2,6-di(4,4'-dipyridyl)-9-thiabicyclo[3.3.1]nonane into discrete 2D supramolecules via coordination-driven self-assembly.

The synthesis and characterization of three new supramolecular complexes 6-8 (a rhomboid and two hexagons) via coordination-driven self-assembly are reported in excellent yields (>90%). These assemblies have 2,6-di(4,4'-dipyridyl)-9-thiabicyclo[3.3.1]nonane 2 as the bridging tecton. All assemblies were characterized by multinuclear NMR (1H and 31P), mass spectrometry (ESI-MS and ESI-FT-ICR), and elemental analysis. The X-ray structure of the 120 degrees tecton 2 is also discussed.

Bridged Bicyclo Compounds↗
PubMed2006

Synthesis of degradable model networks via ATRP and click chemistry.

A simple scheme involving atom transfer radical polymerization (ATRP) from a bifunctional initiator, conversion of the bromine end groups of the resulting telechelic polymer to azides, and cross-linking of this azido-telechelic macromonomer with multi-acetylene functionalized small molecules via copper-catalyzed azide-alkyne cycloaddition was employed to prepare the first tert-butyl acrylate model networks. This general scheme is wide in scope, enabling synthesis of model networks possessing defined pore size from any monomer polymerizable by ATRP. Introduction of an olefin moiety into the ATRP initiator enabled degradation of the materials by ozonolysis to yield star polymer products bearing three or four arms depending on which cross-linker was employed in the parent network. Size-exclusion chromatography of the ozonolysis products confirmed the pore size of the parent network and yielded insight into the number of unreacted functionalities. Model networks derived from a trifunctional alkyne were found to be more completely cross-linked than those derived from a tetrafunctional alkyne, presumably due to less steric hindrance in the former system.

Acrylates↗
PubMed2006

"Click" chemistry in a supramolecular environment: stabilization of organogels by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition.

Organogels are thermoreversible, viscoelastic (soft) materials consisting of low molecular weight compounds which self-assemble into fibers, often of micrometer lengths and nanometer diameters. The installation of terminal azide and alkyne functional groups on the end of a standard alkylamide-based organogelator was found to cause a modest disruption in the gelation properties of the molecule. Cross-linking of those groups by the copper(I)-catalyzed azide-alkyne cycloaddition reaction produced thermoreversible materials of substantially greater gelation temperatures and mechanical rigidity. These results highlight the ability of azides and alkynes-participants in the most commonly used "click" reaction-to function as innocuous precursors to meaningful covalent interactions in materials science.

Alkynes↗
PubMed2005

Systemic trafficking of plant virus nanoparticles in mice via the oral route.

The plant virus, cowpea mosaic virus (CPMV), is increasingly being used as a nanoparticle platform for multivalent display of peptides. A growing variety of applications have employed the CPMV display technology including vaccines, antiviral therapeutics, nanoblock chemistry, and materials science. CPMV chimeras can be inexpensively produced from experimentally infected cowpea plants and are completely stable at 37 degrees C and low pH, suggesting that they could be used as edible or mucosally-delivered vaccines or therapeutics. However, the fate of CPMV particles in vivo, or following delivery via the oral route, is unknown. To address this question, we examined CPMV in vitro and in vivo. CPMV was shown to be stable under simulated gastric conditions in vitro. The pattern of localization of CPMV particles to mouse tissues following oral or intravenous dosing was then determined. For several days following oral or intravenous inoculation, CPMV was found in a wide variety of tissues throughout the body, including the spleen, kidney, liver, lung, stomach, small intestine, lymph nodes, brain, and bone marrow. CPMV particles were detected after cardiac perfusion, suggesting that the particles entered the tissues. This pattern was confirmed using methods to specifically detect the viral capsid proteins and the internal viral RNA. The stability of CPMV virions in the gastrointestinal tract followed by their systemic dissemination supports their use as orally bioavailable nanoparticles.

Administration, Oral↗
PubMed2005

Cu(II)-aza(bisoxazoline)-catalyzed asymmetric benzoylations.

[reaction: see text] Racemic 1,2-diols and alpha-hydroxy carbonyl compounds can be asymmetrically benzoylated in a kinetic resolution in the presence of various Cu(II)-aza(bisoxazoline) catalysts. A novel bisbenzyl-substituted aza(bisoxazoline) ligand proved to be especially effective when immobilized on MeOPEG(5000), giving from 91 to > or = 99% ee in 37-49% yield for each of five sequential reactions.

Journal Article↗
PubMed2005

A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly.

Heteroaryldihydropyrimidines (HAPs) are a new class of antivirals inhibiting production of hepatitis B virus (HBV) virions in tissue culture. Here, we examine the effect of a representative HAP molecule, methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1), on the in vitro assembly of HBV capsid protein (Cp). HAP-1 enhances the rate and extent of Cp assembly over a broad concentration range. Aberrant particles, dominated by hexagonal arrays of Cp, were observed from assembly reactions with high HAP-1 concentrations. HAP-1 also led to dissociation of metastable HBV capsids, overcoming a kinetic barrier to dissociation by scavenging Cp and redirecting its assembly into hexamer-rich structures. Thus, HAP drugs act as allosteric effectors that induce an assembly-active state and, at high concentration, preferentially stabilize noncapsid polymers of Cp. HAP compounds may have multiple effects in vivo stemming from inappropriate assembly of Cp. These results show that activating and deregulating virus assembly may be a powerful general approach for antiviral therapeutics.

Allosteric Regulation↗
PubMed2004

Nucleophilic substitution by grignard reagents on sulfur mustards.

With proper activation of the leaving group, sulfur mustards react with Grignard reagents with neighboring group participation of the sulfur atom. 2,6-Dichloro-9-thiabicyclo[3.3.1]nonane is especially useful in this regard, providing clean reactivity with organomagnesium nucleophiles on a topologically constrained scaffold.

Crystallography, X-Ray↗
PubMed2004

A hierarchy of aryloxide deprotection by boron tribromide.

Aryl propargyl ethers and esters are cleaved selectively in the presence of aryl methyl ethers and esters by boron tribromide in dichloromethane. Under the same conditions, allyl ethers undergo very rapid Claisen rearrangement, and benzyl ethers are also cleaved more rapidly than propargyl. A mechanism involving intramolecular delivery of bromide to the propargyl terminus is proposed. [reaction: see text]

Allyl Compounds↗
PubMed2004

Affinity mass spectrometry from a tailored porous silicon surface.

The development of chemically stable porous silicon (pSi) materials for DIOS (Desorption/Ionization on Silicon) mass spectrometry, covalent linkers cleaved in the DIOS laser pulse, and efficient methods for bond formation to immobilized species, allows for on-chip affinity purification and mass detection.

Porosity↗
PubMed2004

Discovery and characterization of catalysts for azide-alkyne cycloaddition by fluorescence quenching.

Copper-based catalysts for the 1,3-dipolar cycloaddition of azides and alkynes were screened in parallel fashion using a fluorescence quenching assay. The method was designed to identify systems able to accelerate the coupling of reactants at micromolar concentrations in aqueous mixtures and to obtain quantitative comparisons of their activities. In addition to the tris(triazolylamines) previously reported, two types of compounds (bipy/phen and 2-pyridyl Schiff bases) were found to exhibit significant ligand-accelerated catalysis, with one complex showing especially dramatic rate enhancements. Preliminary explorations of the dependence of reaction rate on pH, ligand:Cu ratio, and Cu concentration are described.

Journal Article↗