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Human fibroblasts were induced for interferon synthesis, and the mRNA coding for interferon was partially purified. On this basis, double-stranded DNA copies were synthesized enzymatically and were inserted into cloning vehicles. A large collection of colonies containing chimeric plasmids was obtained. An RNA selection method was used for the identification of several individual clones containing the human fibroblast interferon (IFN-beta) cDNA. From the nucleotide sequence of the cloned structural gene, the primary structure of the mRNA and, hence, of the protein itself was deduced. IFN-beta is a polypeptide 166 amino acids long and contains a single site for N-glycosylation; IFM-beta is normally made as a preinterferon containing a signal sequence that is 21 amino acids long. The interferon gene was inserted into an expression plasmid under thermoinducible control of the phage lambda PL promoter. this allowed the synthesis of polypeptides in the bacteria, which for all physicochemical, biological, and immunologic properties tested closely resembled authentic IFN-beta.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis, antiretrovirus effects and phosphorylation kinetics of 3'-isocyano-3'-deoxythymidine and 3'-isocyano-2',3'-dideoxyuridineJohann Hiebl, Erich Zbiral, Jan Balzarini, and Erik De ClercqCite this: J. Med. Chem. 1990, 33, 2, 845–848Publication Date (Print):February 1, 1990Publication History Published online1 May 2002Published inissue 1 February 1990https://pubs.acs.org/doi/10.1021/jm00164a059https://doi.org/10.1021/jm00164a059research-articleACS PublicationsRequest reuse permissionsArticle Views453Altmetric-Citations25LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

A series of 4-(naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl derivatives (Ia-Im and IIa-IIe) designed as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized via an expeditious route and evaluated for their anti-HIV activities in MT-4 cell cultures. All the synthesized compounds were structurally confirmed by spectral analyses. Biological results showed that three analogues displayed moderate inhibitory activity against wild-type (wt) HIV-1 replication with EC(50) values ranging from 16 to 22 μm. Molecular docking of compound Ih with wt HIV-1 RT was performed to understand the binding mode between these inhibitors and the wt HIV-1 RT and to rationalize some SARs.

We evaluated the predictive value of baseline HIV-1 genotypic resistance mutations for failure of a nucleoside reverse transcriptase inhibitor (NRTI) containing therapy. The change in therapy of 88 HIV-1-infected patients was analyzed retrospectively, relating the genotypic resistance profile at baseline to the evolution of viral load and CD4+ T cell counts. Genotypic resistance at baseline and at 6 months was evaluated with the LiPA HIV-1 RT, which detects mutations at codons 41, 69, 70, 74, 184, and 215. At 1 to 3 months after change in therapy, patients without preexisting resistance mutations to the new drug (group S) had a significantly better evolution in viral load (reduction of 0.37 log(10)) compared with patients with known preexisting resistance mutation(s) (group R) (increase of 0.08 log(10)). This difference was particularly striking for patients with the baseline M184V mutation and whose treatment was modified by the addition of lamivudine. After 6 months the median difference in viral load evolution between the two groups increased to 0.61 log(10): the viral load of patients of group S was still 0.18 log(10) below baseline while patients of group R had an increase of 0.43 log(10) in viral load above baseline. Changes in CD4+ T cell counts were not significantly different. The evolution in viral load in HIV-1-infected patients with and without baseline resistance mutation(s) toward a newly added NRTI is significantly different at 1-3 months and at 6 months after changing or adding one NRTI.

Selective laser melting (SLM) makes use of a high energy density laser beam to melt successive layers of metallic powders in order to create functional parts. The energy density of the laser is high enough to melt refractory metals like Ta and produce mechanically sound parts. Furthermore, the localized heat input causes a strong directional cooling and solidification. Epitaxial growth due to partial remelting of the previous layer, competitive growth mechanism and a specific global direction of heat flow during SLM of Ta result in the formation of long columnar grains with a 〈111〉 preferential crystal orientation along the building direction. The microstructure was visualized using both optical and scanning electron microscopy equipped with electron backscattered diffraction and the global crystallographic texture was measured using X-ray diffraction. The thermal profile around the melt pool was modeled using a pragmatic model for SLM. Furthermore, rotation of the scanning direction between different layers was seen to promote the competitive growth. As a result, the texture strength increased to as large as 4.7 for rotating the scanning direction 90° every layer. By comparison of the yield strength measured by compression tests in different orientations and the averaged Taylor factor calculated using the viscoplastic self-consistent model, it was found that both the morphological and crystallographic texture observed in SLM Ta contribute to yield strength anisotropy.

Multinucleated giant cell (syncytium) formation induced by the interaction between the gp120 glycoprotein expressed on the surface of cells infected with human immunodeficiency virus type (HIV-1) and the CD4 receptor of uninfected CD4-positive (CD4+) cells may play an important role in the depletion of T4 lymphocytes in acquired immune deficiency syndrome (AIDS) patients. Using a double fluorescence cell-staining technique and analysis of the cells by the fluorescence-activated cell sorter (FACS), we have demonstrated that giant cell formation between persistently HIV-1-infected HUT-78 cells and uninfected MOLT-4 cells results in a selective destruction of the uninfected CD4+ MOLT-4 cells. Apparently, bystander CD4+ cells may serve as targets for the killing effect of the HIV-1-infected cells, and this killing effect is preceded by fusion between the target (uninfected) and aggressor (infected) cells. Pentosan polysulfate, dextran sulfate, and various other sulfated polysaccharides, but not heparin, have proved to inhibit this cell fusion process and hence protect the target CD4+ cells against destruction by the killer HIV-1-infected cells. Azidothymidine does not interfere with this process. Assuming that fusion between HIV-infected and uninfected CD4+ cells is a crucial event in the pathogenesis of AIDs, any compounds that specifically interfere with this process may be therapeutically advantageous in the treatment of this disease.

Beginning with 3-cyclopenten-1-ylamine hydrochloride, the 5'-nor derivatives of carbocyclic 2'-deoxyguanosine (2), 2'-deoxyadenosine (3), and 2,6-diaminopurine 2'-deoxyribofuranoside (4) have been prepared. These compounds were evaluated for antiviral potential versus herpes simplex virus, varicella-zoster virus, cytomegalovirus, vaccinia virus, vesicular stomatitis virus, and human immunodeficiency virus and found to lack activity. Also, compounds 2-4 were virtually nontoxic toward the host (human diploid fibroblast ESM and HEL) cells. These biological properties may be due to the inability of 2-4 to be phosphorylated to the requisite nucleotide level that is likely to be necessary for biological activity by correlation to carbocyclic 2'-deoxyguanosine (1), which possesses significant antiviral properties as a result of conversion to its 5'-triphosphate derivative.