The anti-hepatitis B (anti-HBV) activities of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (2'-deoxy-3'-thia-5-fluorocytosine [FTC]) were studied by using an HBVtransfected cell line (HepG2 derivative 2.2.15, subclone P5A). The (-) isomer was found to be a potent inhibitor of viral replication, with an apparent 50% inhibitory concentration of 10 nM, whfle the (+) isomer was found to be considerably less active. Both isomers showed miimal toxicity to HepG2 cells (50% inhibitory concentration, >200 a.M) and showed minimal toxicity in the human bone marrow progenitor cell assay. In accord with the cellular antiviral activity data, the 5'-triphosphate of (-)-FIC inhibited viral DNA synthesis in an endogenous HBV DNA polymerase assay, while the 5'-triphosphate of the (+) isomer was inactive.Unphosphorylated (-)-FTC did not inhibit product formation in the endogenous assay, souggestng that the antiviral activity of the compound is dependent on anabolism to the 5'-triphosphate. Both (-)-and (+)-FTC were anabolized to the corresponding 5'-triphosphates in chronically HBV-infected HepG2 celLs. The rate of accumulation and the steady-state concentration of the 5'-triphosphate of (-)-FTC were greater. Also, (-)-FTC was not a substrate for cytidine deaminase and, therefore, is not subject to d tion and conversion to an inactive uridine analog. The (+) isomer is, however, a good substrate for cytidine deaminase.Hepatitis B virus (HBV), the causative agent of acute and chronic hepatitis, directly affects about 5% of the world's population. Chronic carriers of HBV are at an increased risk of liver damage that, in the worst cases, can lead to cirrhosis of the liver and/or to hepatocellular carcinoma. Vaccination against HBV is one way to effectively prevent HBV infection. However, vaccination is not an effective therapy for the estimated 200 million chronic carriers. Although several antiviral agents such as alpha interferon, adenine arabinoside monophosphate, and acyclovir have been tested as therapeutic agents, only alpha interferon has demonstrated some promise (7,8,9,17,23,25).The replication cycle of hepadnaviruses includes the reverse transcription of an RNA template (6). This process is catalyzed by a polymerase that shares significant sequence homology with the reverse transcriptase from retroviruses (17). As a consequence, it has been demonstrated that a number of compounds that inhibit human immunodeficiency virus (HIV) replication in vitro (for example, 2',3'-dideoxycytidine) also inhibit HBV replication in vitro (4,14,15,18,24). These agents await further study to determine their usefulness as therapeutic agents for the treatment of HBV infections.Here we report the anti-HBV activities, cytotoxicities, and anabolism of the resolved enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC) (Fig. 1). The anti-HBV activity of the racemic material has been reported previously (4). Our results show that the * Corresponding authors. antiviral activ...

SUMMARY Stroke remains a significant problem despite decades of work on neuroprotective strategies. NMDA receptor (NMDAR) antagonists are neuroprotective in preclinical models, but have been clinically unsuccessful, in part due to side effects. Here we describe a prototypical GluN2B-selective antagonist with an IC50 value that is 10-fold more potent at acidic pH 6.9 associated with ischemic tissue compared to pH 7.6, a value close to the pH in healthy brain tissue. This should maximize neuroprotection in ischemic tissue while minimizing on-target side-effects associated with NMDAR blockade in non-injured brain regions. We have determined the mechanism underlying pH-dependent inhibition and demonstrate the utility of this approach in vivo. We also identify dicarboxylate dimers as a novel proton sensor in proteins. These results provide insight into the molecular basis of pH-dependent neuroprotective NMDAR block, which could be beneficial in a wide range of neurological insults associated with tissue acidification.

A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3−650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1 IIIB virus in MAGI-CCR5/ CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.

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The development of a biomimetic active hydrofoil that utilizes shape memory alloy (SMA) actuator technology is presented. This work is the first stage prototype of a vehicle that will consist of many actuated body segments. The current work describes the design, modeling and testing of a single-segment demonstration SMA actuated hydrofoil. The SMA actuation elements are two sets of thin wires on either side of an elastomeric component that joins together the leading and trailing edges of the hydrofoil. Controlled heating and cooling of the two wire sets generates bi-directional bending of the elastomer, which in turn deflects the trailing edge of the hydrofoil. In this paper the design of the hydrofoil and the experimental tests preformed thereon are explained. A detailed account of SMA actuator preparation (training) and material characterization is given. Finite-element method (FEM) modeling of hydrofoil response to electrical heating of the SMA actuators is carried out using a thermomechanical constitutive model for the SMA with input from the material characterization. The modeling predictions are finally compared with experimental measurements of the trailing edge deflection and the SMA actuator temperature.