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Featured researches published by Anne B. Eldrup.


Journal of Biological Chemistry | 2003

Inhibition of Hepatitis C Virus RNA Replication by 2′-Modified Nucleoside Analogs

Steven S. Carroll; Joanne E. Tomassini; Michele Bosserman; Krista Getty; Mark Stahlhut; Anne B. Eldrup; Balkrishen Bhat; Dawn L. Hall; Amy L. Simcoe; Robert L. Lafemina; Carrie A. Rutkowski; Bohdan Wolanski; Zhucheng Yang; Giovanni Migliaccio; Raffaele De Francesco; Lawrence C. Kuo; Malcolm Maccoss; David B. Olsen

The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is essential for the replication of viral RNA and thus constitutes a valid target for the chemotherapeutic intervention of HCV infection. In this report, we describe the identification of 2′-substituted nucleosides as inhibitors of HCV replication. The 5′-triphosphates of 2′-C-methyladenosine and 2′-O-methylcytidine are found to inhibit NS5B-catalyzed RNA synthesis in vitro, in a manner that is competitive with substrate nucleoside triphosphate. NS5B is able to incorporate either nucleotide analog into RNA as determined with gel-based incorporation assays but is impaired in its ability to extend the incorporated analog by addition of the next nucleotide. In a subgenomic replicon cell line, 2-C-methyladenosine and 2′-O-methylcytidine inhibit HCV RNA replication. The 5′-triphosphates of both nucleosides are detected intracellularly following addition of the nucleosides to the media. However, significantly higher concentrations of 2′-C-methyladenosine triphosphate than 2′-O-methylcytidine triphosphate are detected, consistent with the greater potency of 2′-C-methyladenosine in the replicon assay, despite similar inhibition of NS5B by the triphosphates in the in vitroenzyme assays. Thus, the 2′-modifications of natural substrate nucleosides transform these molecules into potent inhibitors of HCV replication.


Antimicrobial Agents and Chemotherapy | 2004

A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

David B. Olsen; Anne B. Eldrup; Linda Bartholomew; Balkrishen Bhat; Michele Bosserman; Alessandra Ceccacci; Lawrence F. Colwell; John F. Fay; Osvaldo A. Flores; Krista Getty; Jay A. Grobler; Robert L. Lafemina; Eric J. Markel; Giovanni Migliaccio; Marija Prhavc; Mark Stahlhut; Joanne E. Tomassini; Malcolm Maccoss; Daria J. Hazuda; Steven S. Carroll

ABSTRACT Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2′-C-methyl-adenosine and 2′-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2′-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5′-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2′-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2′-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2′-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.


Antimicrobial Agents and Chemotherapy | 2005

Inhibitory Effect of 2′-Substituted Nucleosides on Hepatitis C Virus Replication Correlates with Metabolic Properties in Replicon Cells

Joanne E. Tomassini; Krista Getty; Mark Stahlhut; Sung Shim; Balkrishen Bhat; Anne B. Eldrup; Thazha P. Prakash; Steven S. Carroll; Osvaldo A. Flores; Malcolm Maccoss; Daniel R. McMasters; Giovanni Migliaccio; David B. Olsen

ABSTRACT Nucleosides have been widely used in the treatment of viral diseases, but relatively few have been identified as inhibitors of hepatitis C virus (HCV). The modified ribonucleosides, 2′-C-methyl-adenosine and 2′-O-methyl-cytidine, are potent inhibitors of HCV replication which specifically target the NS5B polymerase. Herein, a more extensive characterization of the effect of these compounds upon HCV replication in subgenomic replicons is reported. A highly selective antireplicative effect induced by the nucleosides in replicon-containing cell lines was maintained during an exponential growth period with potencies which paralleled the reduction of both positive- and negative-strand RNA replication. Moreover, the inhibitory effect closely correlated with the intrinsic metabolic properties of differing replicon clonal lines. Interestingly, while 2′-C-methyl-adenosine elicited similar inhibitory potencies in different cell lines, 2′-O-methyl-cytidine was found to be inactive in one replicon cell line tested, although the corresponding triphosphates comparably inhibited the in vitro activity of replication complexes isolated from these cells and the activity of NS5B polymerase using synthetic templates. The lack of antireplicative effect, attributed to poor intracellular conversion of the 2′-O-methyl-cytidine nucleoside to the active 5′-triphosphate, was reversed using a monophosphate prodrug. Thus, although replicon cells are useful for evaluating the effect of inhibitors upon HCV replication, these findings have important implications for their use in the identification and characterization of nucleosides and other chemotherapeutic agents requiring cellular metabolism.


Journal of Medicinal Chemistry | 2009

Structure-Based Optimization of Arylamides as Inhibitors of Soluble Epoxide Hydrolase

Anne B. Eldrup; Fariba Soleymanzadeh; Steven John Taylor; Ingo Muegge; Neil A. Farrow; David B. Joseph; Keith McKellop; Chuk Chui Man; Alison Kukulka; Stéphane De Lombaert

Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of an effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection. The screen identified N-(3,3-diphenyl-propyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.


Journal of Medicinal Chemistry | 2012

Identification of a Potent Sodium Hydrogen Exchanger Isoform 1 (NHE1) Inhibitor with a Suitable Profile for Chronic Dosing and Demonstrated Cardioprotective Effects in a Preclinical Model of Myocardial Infarction in the Rat

John D. Huber; Jörg Bentzien; Stephen Boyer; Jennifer Burke; Stéphane De Lombaert; Christian Eickmeier; Xin Guo; James V. Haist; Eugene R. Hickey; Paul Kaplita; Morris Karmazyn; Raymond A. Kemper; Charles A. Kennedy; Thomas M. Kirrane; Jeffrey B. Madwed; Elizabeth Mainolfi; Nelamangara Nagaraja; Fariba Soleymanzadeh; Alan David Swinamer; Anne B. Eldrup

Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.


Archive | 2002

Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase

Balkrishen Bhat; Neelima Bhat; Anne B. Eldrup; Thazha P. Prakash; Marija Prhavc; Quanlai Song; Phillip Dan Cook; Steven S. Carroll; Malcolm Maccoss; David B. Olsen


Journal of Biological Chemistry | 2003

Characterization of Resistance to Non-obligate Chain-terminating Ribonucleoside Analogs That Inhibit Hepatitis C Virus Replication in Vitro

Giovanni Migliaccio; Joanne E. Tomassini; Steven S. Carroll; Licia Tomei; Sergio Altamura; Balkrishen Bhat; Linda Bartholomew; Michele Bosserman; Alessandra Ceccacci; Lawrence F. Colwell; Riccardo Cortese; Raffaele De Francesco; Anne B. Eldrup; Krista Getty; Xiaoli S. Hou; Robert L. Lafemina; Steven W. Ludmerer; Malcolm Maccoss; Daniel R. McMasters; Mark Stahlhut; David B. Olsen; Daria J. Hazuda; Osvaldo A. Flores


Archive | 2003

Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation

Charles Allerson; Balkrishen Bhat; Anne B. Eldrup; Muthiah Manoharan; Richard H. Griffey; Brenda F. Baker; Eric E. Swayze


Archive | 2003

Compositions comprising alternating 2’-modified nucleosides for use in gene modulation

Charles Allerson; Balkrishen Bhat; Anne B. Eldrup; Muthiah Manoharan; Richard H. Griffey; Brenda F. Baker; Eric E. Swayze


Journal of Medicinal Chemistry | 2004

Structure-activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase.

Anne B. Eldrup; Charles Allerson; C. Frank Bennett; Sanjib Bera; Balkrishen Bhat; Neelima Bhat; Michele Bosserman; Jennifer L. Brooks; Christine Burlein; Steven S. Carroll; P. Dan Cook; Krista Getty; Malcolm Maccoss; Daniel R. McMasters; David B. Olsen; Thazha P. Prakash; Marija Prhavc; Quanlai Song; Joanne E. Tomassini; Jie Xia

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Muthiah Manoharan

Howard Hughes Medical Institute

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