Publications by authors named "Ravi Rajagopalan"

A total synthesis of N-desmethyl thalassospiramide C, a unique strained macrocyclic proteobacterial depsipeptide, enabled a detailed crystallographic study of its covalent complex with cathepsin K, a member of a medicinally important family of cysteine proteases. The study provides support for the mechanism of action, and the insight gained can be used for structure-based drug design targeting these calpain proteases.

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The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures.

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The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.

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Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle.

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Purpose: To demonstrate that endovenous thermal ablation is not only effective and safe but also a durable treatment in patients with symptomatic varicose veins.

Methods: From February 2002 to February 2009, 2354 patients (1836 women; mean age 53 years, range 15-95) with symptomatic varicose veins in 3000 limbs underwent endovenous laser ablation (EVLA) or radiofrequency ablation (RFA). The majority of treated vessels were the great saphenous veins (GSV; 2619, 87.

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The hepatitis C virus (HCV) nonstructural protein 3 (NS3) is known to possess multiple enzymatic activities. In addition to its well-characterized protease activity, HCV NS3 also has ATP hydrolase (ATPase) and nucleic acid unwinding (helicase) activities. We systematically studied the effect of common reagents on all three enzymatic activities with a view to improving assay sensitivity for compound screening and profiling.

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2-(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl)-1-hydroxynaphthalene derivatives as potential anti-HCV drugs targeting NS5B polymerase have been investigated. Their synthesis, HCV NS5B polymerase inhibition and replicon activity are discussed.

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3-(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl)-4-hydroxy-2H-quinolizin-2-one derivatives as potential anti-HCV drugs targeting NS5B polymerase have been investigated. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.

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The protease activity of hepatitis C virus nonstructural protein 3 (NS3) is essential for viral replication. ITMN-191, a macrocyclic inhibitor of the NS3 protease active site, promotes rapid, multilog viral load reductions in chronic HCV patients. Here, ITMN-191 is shown to be a potent inhibitor of NS3 with a two-step binding mechanism.

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Purpose: To evaluate the effectiveness of endovenous treatment of symptomatic varicose veins using the endovenous laser (EVL) or radiofrequency (RF) energy over a >3-year follow-up.

Methods: From February 2002 to August 2005, 981 consecutive patients (770 women; mean age 51 years, range 15-90) with symptomatic varicose veins in 1250 lower limbs underwent endovenous ablation of 1149 great saphenous veins (GSV) and 101 small saphenous veins (SSV) under tumescent anesthesia without intravenous sedation or regional anesthesia. There were 990 GSV and 101 SSV procedures using EVL; 159 GSVs were treated with RF energy.

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Purpose: To report early results of a single-center experience with endovenous laser ablation of the saphenous vein (ELAS).

Methods: From February 2002 to January 2003, 165 eligible patients (116 women; mean age 59.1 years, range 27-90) were treated with ELAS for venous insufficiency in 203 lower limbs.

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Purpose: To describe a technique for deploying an AneuRx stent-graft in an abdominal aortic aneurysm (AAA) with an acutely angled aortic neck.

Technique: In routine cases, the AneuRx stent-graft main body is positioned with the nose cone notch facing the contralateral side. In severely angulated aortic necks, however, the main body of the AneuRx stent-graft can be positioned with the nose cone notch and iliac limb gate facing the ipsilateral side; this dramatically reduces the acuity of the angle at the aortic neck and the iliac gate.

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Purpose: To compare a single-center experience with the AneuRx stent-graft system before and after FDA approval to results from the multicenter phase II clinical trial.

Methods: The medical records of 230 consecutive patients (218 men; mean age 74 years) undergoing AneuRx stent-graft implantation for abdominal aortic aneurysm (AAA) exclusion since September 1999 were reviewed to collect patient characteristics, aneurysm morphology, procedure variables, perioperative morbidity, mortality, and short-term outcome. These data were compared to the 30 patients treated at our institution during the AneuRx phase II clinical trial and to the overall multicenter trial data.

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Purpose: The purpose of this study was to describe our experience with endoluminal graft repair of a variety of thoracic aorta pathologies with a commercially developed device currently under investigation. Our patient population included patients eligible for open surgical repair and those with prohibitive surgical risk.

Methods: From February 2000 to February 2001, endovascular stent-graft repair of the thoracic aorta was performed in 46 patients (mean age, 70 years; 29 male and 17 female patients) with the Gore Excluder.

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We have created a federated database for genome studies of Magnaporthe grisea, the causal agent of rice blast disease, by integrating end sequence data from BAC clones, genetic marker data and BAC contig assembly data. A library of 9216 BAC clones providing >25-fold coverage of the entire genome was end sequenced and fingerprinted by HindIII digestion. The Image/FPC software package was then used to generate an assembly of 188 contigs covering >95% of the genome.

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A direct UV-VIS spectrophotometric assay has been developed for peptide deformylase. This assay employs a novel class of peptide mimetics as deformylase substrates which, upon enzymatic removal of the N-terminal formyl group, rapidly release free thiols. The released thiols are quantitated using Ellman's reagent.

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