The synthesis of a series of novel 1-(2-deoxy-4-thio-beta-D-erythro-pentofuranosyl)-(6-azapyrimidine) nucleosides is described. X-ray crystallographic data of the thymidine derivative allowed conformational analysis, which indicated a twist (3T2) sugar conformation. Hydrogen-bonded assemblies for the crystal structure were determined using PLATON software to allow further interpretation of the crystal packing and base interactions. The 6-azapyrimidine nucleosides described were evaluated against a range of viral strains. The thymidine analogue showed pronounced activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and vaccinia virus. This compound lost only 5- to 10-fold of its antiviral activity against thymidine kinase (TK)-deficient HSV-1 and VZV strains. These observations suggest that the compounds may not entirely depend on viral TK-catalyzed phosphorylation for antiviral activity and/or use an alternative metabolic activation pathway, and/or display a unique mechanism of antiviral action by the unmetabolized nucleoside analogue.
Miao Miao,1 Xixi Jing,1 Erik De Clercq,2 Guangdi Li1 1Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410078, People’s Republic of China; 2Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven 3000, BelgiumCorrespondence: Guangdi Li Email liguangdi.research@gmail.comAbstract: On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b – the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.Keywords: danoprevir, ITMN-191, R7227, HCV NS3/4A inhibitor, HCV genotype
Biomanufacturing integrates life science and engineering fundamentals to produce biocompatible products enhancing the quality of life. The state-of-the-art of this rapidly evolving manufacturing sector is presented and discussed, in particular the additive electrical, chemical and physical processes currently being applied to produce synthetic and biological parts. This fabrication strategy is strongly material-dependent, so the main classes of biomaterials are detailed. It is explained the potential to process composite materials combining synthetic and biological materials, such as cells, proteins and growth factors, as well the interdependences between materials and processes. The techniques commonly used to increase the bioactivity of clinical implants and improve the interface characteristics between biological tissues and implants are also presented.
No abstract is provided for this article.
Antiviral therapy and, particularly, anti-HIV therapy has definitely come of age [1]. There are now more than 30 compounds that have been formally approved for the therapy of virus infections. The nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir are used in the treatment of human immunodeficiency virus (HIV) infections and lamivudine is also licensed for the treatment of hepatitis B virus (HBV) infections. The nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir has been approved for the treatment of HIV infections and is also effective againstHBVinfections. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, delavirdine and efavirenz are exclusively used in the treatment of HIV infections, and so are the HIV protease inhibitors (PIs) saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir.
Abstract 5-Ethyl-2′-deoxyurldine (EDU) is phosphorylated to a much greater extent by herpes simplex virus (HSV)-infected Vero cells than by mock-infected cells. Within the infected cells, EDU is preferentially incorporated into viral DNA and more inhibitory to viral than cellular DNA synthesis
The destruction of the immune system by progressive loss of CD4 T cells is the hallmark of AIDS. CCR5-dependent (R5) human immunodeficiency virus type 1 (HIV-1) isolates predominate in the early, asymptomatic stages of HIV-1 infection, while CXCR4-dependent (X4) isolates typically emerge at later stages, frequently coinciding with a rapid decline in CD4 T cells. Lymphocyte killing in vivo primarily occurs through apoptosis, but the importance of apoptosis of HIV-1-infected cells relative to apoptosis of uninfected bystander cells is controversial. Here we show that in human lymphoid tissues ex vivo, apoptosis of uninfected bystander CD4 T cells is a major mechanism of lymphocyte depletion caused by X4 HIV-1 strains but is only a minor mechanism of depletion by R5 strains. Further, X4 HIV-1-induced bystander apoptosis requires the interaction of the viral envelope glycoprotein gp120 with the CXCR4 coreceptor on CD4 T cells. These results emphasize the contribution of bystander apoptosis to HIV-1 cytotoxicity and suggest that in association with a coreceptor switch in HIV disease, T-cell killing evolves from an infection-restricted stage to generalized toxicity that involves a high degree of bystander apoptosis.
Le but de cette etude est d'analyser les performances des differentes sources laser disponibles pour le frittage selectif direct au laser des poudres metalliques sans aucun liant polymere. Pour cela, on a fritte des pieces bidimensionnelles (c'est-a-dire en une seule couche) de differents melanges de poudres acier-cuivre; et les differentes proprietes de ces pieces ont ete analysees. Dans cet article, on a compare en detail le laser Nd:YAG avec le laser Co 2 . On a pu en conclure que le laser Nd:YAG donnait de meilleurs resultats que le laser Co 2 pour le frittage direct en phase liquide de pieces en acier-cuivre.
An experimental model of herpetic infection based on intranasal challenge of 12-day-old mice with herpes simplex virus (type 1) has been developed for assessment of the efficacy of a variety of antiviral compounds with clinical potential: cytosine arabinoside, adenine arabinoside, iododeoxyuridine, ribavirin, chloriteoxidized oxyamylose, polyriboinosinic-polyribocytidylic acid, and interferon. The model employed is reminiscent of herpetic encephalitis in humans in both the portal of entry (nasopharyngeal cavity) and the mode of transmission (nerve route) of the virus to the target organ (brain). The mortality rate from viral infection was significantly reduced (greater than or equal to 30%) by the following treatment regimens: cytosine arabinoside, adenine arabinoside, iododeoxyuridine, and ribavirin, administered daily for seven consecutive days starting immediately after inoculation of virus, at dosage levels of 4-20 mg/kg, 20-100mg/kg, 100mg/kg, and 20-100 mg/kg, respectively; and chlorite-oxidized oxyamylose, polyriboinosinic-polyribocytidylic acid, and mouse interferon, administered 24 hr before viral challenge, as single doses of 100-500 mg/kg, 20mg/kg, and 10(7)-10(8) international reference units/kg respectively. Similar doses of polyriboinosinic-polyribocytidylic acid and mouse interferon administered after inoculation of virus did not alter the final mortality rate.
SUMMARY Various double-stranded RNAs of either synthetic or natural origin have been compared for their interferon-inducing potency in human skin fibroblasts ‘primed’ with interferon and ‘superinduced’ with cycloheximide and actinomycin D. While natural double-stranded RNAs (extracted from either Penicillium chrysogenum mycophage, f2 bacteriophage or reovirus) and alternating copolymers [(A-U)n.(A-U)n, (G-C)n.(G-C)n, (I-C)n.(I-C)n]* proved relatively less effective in inducing interferon than (I)n.(C)n, a variety of synthetic homopolymer pairs, including (I)n.(br5C)n, (I)n.(s2C)n, (A)n.(rT)n and (A)n.(U)n, showed an interferon-inducing activity comparable to that of (I)n.(C)n.
