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1.
Antimicrob Agents Chemother ; 56(1): 271-9, 2012 Jan.
Article En | MEDLINE | ID: mdl-22064535

Danoprevir is a hepatitis C virus (HCV) NS3/4A protease inhibitor that promotes multi-log(10) reductions in HCV RNA when administered as a 14-day monotherapy to patients with genotype 1 chronic HCV. Of these patients, 14/37 experienced a continuous decline in HCV RNA, 13/37 a plateau, and 10/37 a rebound. The rebound and continuous-decline groups experienced similar median declines in HCV RNA through day 7, but their results diverged notably at day 14. Plateau group patients experienced a lesser, but sustained, median HCV RNA decline. Baseline danoprevir susceptibility was similar across response groups but was reduced significantly at day 14 in the rebound group. Viral rebound in genotype 1b was uncommon (found in 2/23 patients). Population-based sequence analysis of NS3 and NS4A identified treatment-emergent substitutions at four amino acid positions in the protease domain of NS3 (positions 71, 155, 168, and 170), but only two (155 and 168) were in close proximity to the danoprevir binding site and carried substitutions that impacted danoprevir potency. R155K was the predominant route to reduced danoprevir susceptibility and was observed in virus isolated from all 10 rebound, 2/13 plateau, and 1/14 continuous-decline patients. Virus in one rebound patient additionally carried partial R155Q and D168E substitutions. Treatment-emergent substitutions in plateau patients were less frequently observed and more variable. Single-rebound patients carried virus with R155Q, D168V, or D168T. Clonal sequence analysis and drug susceptibility testing indicated that only a single patient displayed multiple resistance pathways. These data indicate the ascendant importance of R155K for viral escape during danoprevir treatment and may have implications for the clinical use of this agent.


Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Lactams/administration & dosage , Protease Inhibitors/administration & dosage , Sulfonamides/administration & dosage , Viral Nonstructural Proteins/genetics , Viral Proteins/genetics , Amino Acid Substitution , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Cyclopropanes , Drug Administration Schedule , Drug Resistance, Viral/drug effects , Genotype , Hepacivirus/enzymology , Hepatitis C, Chronic/virology , Humans , Isoindoles , Lactams/therapeutic use , Lactams, Macrocyclic , Models, Molecular , Molecular Typing , Mutation , Proline/analogs & derivatives , Protease Inhibitors/therapeutic use , Protein Structure, Tertiary , RNA, Viral/analysis , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recurrence , Species Specificity , Sulfonamides/therapeutic use , Viral Load/drug effects , Viral Nonstructural Proteins/metabolism , Viral Proteins/metabolism , Virus Replication/drug effects
2.
Langmuir ; 22(10): 4846-52, 2006 May 09.
Article En | MEDLINE | ID: mdl-16649806

Phosphorus modification of a HZSM-5 (MFI) zeolite by wet impregnation has long been known to decrease aromatic formation in methanol conversion chemistry. We prepared and studied a catalyst modified by introducing trimethylphosphine under reaction conditions followed by oxidation. Magic-angle spinning (MAS) NMR shows that extensive dealumination occurs, resulting in a catalyst with a much higher framework SiO2/Al2O3 ratio, as well as extraframework aluminum and approximately 1.4 equiv of entrained phosphoric acid (under working conditions) per aluminum. Upon dehydration or regeneration, the phosphoric acid is converted, reversibly, to entrained P4O10. The aromatic selectivity of the modified catalyst is significantly lower than that of an unmodified zeolite with a similar, increased framework SiO2/Al2O3 ratio. By comparing the rates of H/D exchange in propene under conditions similar to those in methanol conversion chemistry, we determined that the acid site strength is indistinguishable on modified and unmodified zeolites, and this is consistent with theoretical modeling. On the phosphorus-modified zeolite, the rate of propene oligomerization is greatly suppressed, suggesting that entrained phosphate is an impediment to sterically demanding reactions.

3.
J Am Chem Soc ; 126(9): 2991-3001, 2004 Mar 10.
Article En | MEDLINE | ID: mdl-14995217

Recent experimental work has shown that methanol to olefin (MTO) catalysis on microporous solid acids proceeds through a hydrocarbon pool mechanism with methylbenzenes frequently acting as the most important reaction centers. Other recent experimental evidence suggests that side-chain methylation is more important than an alternative paring (ring contraction-expansion) mechanism. The present investigation uses density functional theory B3LYP/cc-pVTZ//B3LYP/6-311G and G3(MP2) calculations to model many of the features of the side-chain mechanism. We first calculated at the G3(MP2) level the heats of formation of 43 neutral alkybenzenes to predict the thermodynamics for methylation reactions. The G3(MP2) results predict that sequential methylation of benzene rings with fewer than four methyl groups will preferentially occur on the ring, resulting in the series toluene, 1,3-dimethylbenzene, 1,2,4-trimethylbenzene, and 1,2,4,5-tetramethylbenzene. With the addition of another methyl group side-chain methylation becomes preferred, with 1-ethyl-2,4,5-tetramethylbenzene predicted to be more stable than pentamethylbenzene by 0.7 kcal/mol. We modeled the entire gas-phase side-chain reaction mechanism at the B3LYP/cc-pVTZ//B3LYP/6-311G level, using p-xylene, 1,2,3,5-tetramethylbenzene, and hexamethylbenzene as reaction centers and following the reaction to the point of producing both ethylene and propene. B3LYP/6-311G analytical frequencies were calculated in order to obtain the data needed for the prediction of enthalpies. For comparison, G3(MP2) enthalpies were also calculated for the mechanism based on p-xylene only. We also used a zeolite cluster model to more accurately describe the relative energetics of the reaction for the entire hexamethylbenzene mechanism and parts of the p-xylene mechanism. These calculations place the side-chain mechanism on a much stronger foundation and reproduce experimental structure-reactivity and structure-selectivity data for the methylbenzene hydrocarbon pool.

4.
Acc Chem Res ; 36(5): 317-26, 2003 May.
Article En | MEDLINE | ID: mdl-12755641

The process of converting methanol to hydrocarbons on the aluminosilicate zeolite HZSM-5 was originally developed as a route from natural gas to synthetic gasoline. Using other microporous catalysts that are selective for light olefins, methanol-to-olefin (MTO) catalysis may soon become central to the conversion of natural gas to polyolefins. The mechanism of methanol conversion proved to be an intellectually challenging problem; 25 years of fundamental study produced at least 20 distinct mechanisms, but most did not account for either the primary products or a kinetic induction period. Recent experimental and theoretical work has firmly established that methanol and dimethyl ether react on cyclic organic species contained in the cages or channels of the inorganic host. These organic reaction centers act as scaffolds for the assembly of light olefins so as to avoid the high high-energy intermediates required by all "direct" mechanisms. The rate of formation of the initial reaction centers, and hence the duration of the kinetic induction period, can be governed by impurity species. Secondary reactions of primary olefin products strongly reflect the topology and acid strength of the microporous catalyst. Reaction centers form continuously through some secondary pathways, and they age into polycyclic aromatic hydrocarbons, eventually deactivating the catalyst. It proves useful to consider each cage (or channel) with its included organic and inorganic species as a supramolecule that can react to form various species. This view allows us to identify structure-activity and structure selectivity relationships and to modify the catalyst with degrees of freedom that are more reminiscent of homogeneous catalysis than heterogeneous catalysis.

5.
J Am Chem Soc ; 125(4): 866-7, 2003 Jan 29.
Article En | MEDLINE | ID: mdl-12537474

The first Raman spectrum of an adsorbed carbenium ion has been measured: The 1,3-dimethylcyclopentenyl cation adsorbed in zeolite H-MFI. 1,3-Dimethylcyclopentenyl cation has been observed as a component of the hydrocarbon pool formed during the methanol-to-gasoline process catalyzed by zeolite H-MFI. The Raman shifts recorded for 1,3-dimethylcyclopentenyl cation are in remarkable agreement with computer calculations of the vibrational band positions for the isolated cation. This agreement suggests that the cation is unperturbed by interactions with the zeolite pore walls so that Raman spectra of free or solution-phase hydrocarbons can be used to identify these same species adsorbed in zeolite pores.

6.
Biochem Pharmacol ; 65(1): 1-8, 2003 Jan 01.
Article En | MEDLINE | ID: mdl-12473372

The identification of small molecule antagonists of protein function is at the core of the pharmaceutical industry. Successful approaches to this problem, including screening and rational design, have been developed over the years to identify antagonists of enzymes and cellular receptors. These methods have been extended to the search for inhibitors of protein-protein interactions. While the very possibility of designing a small molecule inhibitor for such interactions was once doubted, there are examples of such inhibitors that are currently marketed products and many more inhibitors in various stages of research and development. Here we review the progress in identifying and designing small molecule protein inhibitors, with particular attention to those that block protein-protein interactions. We also discuss the physical character of protein-protein interfaces, and the resulting implications for small molecule lead discovery and design.


Drug Design , Enzyme Inhibitors/pharmacology , Proteins/antagonists & inhibitors , Amino Acids/chemistry , Binding Sites , Computational Biology , Kinetics , Protein Binding , Receptors, Cell Surface/antagonists & inhibitors , Static Electricity
7.
Bioorg Med Chem Lett ; 12(20): 2913-7, 2002 Oct 21.
Article En | MEDLINE | ID: mdl-12270174

Two structural classes of dual alpha4beta1/alpha4beta7 integrin antagonists were investigated via solid-phase parallel synthesis. Using an acylated amino acid backbone, lead compounds containing biphenylalanine or tyrosine carbamate scaffolds were optimized for inhibition of alpha4beta1/VCAM and alpha4beta7/MAdCAM. A comparison of the structure-activity relationships in the inhibition of the alpha4beta7/MAdCAM interaction for substituted amines employed in both scaffolds suggests a similar binding mode for the compounds.


Integrin alpha4beta1/antagonists & inhibitors , Integrins/antagonists & inhibitors , Combinatorial Chemistry Techniques , Drug Design , Enzyme-Linked Immunosorbent Assay , Indicators and Reagents , Integrin alpha4beta1/chemistry , Integrins/chemistry , Models, Molecular , Molecular Conformation , Structure-Activity Relationship
8.
J Am Chem Soc ; 124(36): 10868-74, 2002 Sep 11.
Article En | MEDLINE | ID: mdl-12207542

Assessing the degree of proton transfer from a Brønsted acid site to one or more adsorbed bases is central to arguments regarding the strength of zeolites and other solid acids. In this regard certain solid-state NMR measurements have been fruitful; for example, some (13)C, (15)N, or (31)P resonances of adsorbed bases are sensitive to protonation, and the (1)H chemical shift of the Brønsted site itself reflects hydrogen bonding. We modeled theoretically the structures of adsorption complexes of several bases on zeolite HZSM-5, calculated the quadrupole coupling constants (Q(cc)) and asymmetry parameters (eta) for aluminum in these complexes and then in turn simulated the central transitions of their (27)Al MAS NMR spectra. The theoretical line width decreased monotonically with the degree of proton transfer, reflecting structural relaxation around aluminum as the proton was transferred to a base. We verified this experimentally for a series of adsorbed bases by way of single-pulse MAS and triple quantum MQMAS (27)Al NMR. The combined theoretical and experimental approach described here provides a strategy by which (27)Al data can be applied to resolve disputed interpretations of proton transfer based on other evidence.

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