Publications

Prostratin, a non-tumour promoting phorbol ester, exhibit a potent anti-HIV activity against human immunodeficiency virus type 1 (HIV-1). However, the antiviral mechanism of prostratin is not well defined. In the present study, we report that prostratin exhibits potent antiviral activity against different strains of HIV-1 (subtypes B and D), a clinical HIV isolate (L1), HIV-2 (ROD and EHO) and SIV (MAC251) with EC50-values ranging from 0.02-0.09 microg/ml. Prostratin was equally active against HIV strains resistant to the polyanionic binding inhibitor dextran sulphate, the fusion inhibitor T-20 (enfuvirtide), nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs). In contrast, prostratin lost 4.4- and 6.8-fold of its effect against the HIV strains resistant to AMD3100 and the quaternary ammonium salt QAS10+, respectively. As shown by time-of-addition experiments, prostratin needs to be present at the time of viral adsorption to exert its antiviral activity. We selected an HIV strain (NL4.3/PROS) resistant to prostratin in MT-4 cells. The sensitivity of NL4.3/PROS towards prostratin, dextran sulphate and QAS10+ was reduced by 3.2, 4.1 and >50-fold, respectively. However, NL4.3/ PROS was still sensitive to AMD3100, T-20, NRTIs (zidovudine and nevirapine) and a PI (ritonavir). Recombination of the gp160-gene of the NL4.3/PROS strain in a NL4.3 wild-type molecular clone fully rescued its phenotypic resistance. DNA sequencing of the NL4.3/PROS strain revealed mutations throughout the gp120 gene previously associated with resistance towards other HIV entry inhibitors. We concluded that prostratin inhibits the entry step of the replication cycle of HIV by interacting with a cellular target necessary for viral entry.

The novel aza-analogues of tiazofurin (TZF) with 2-[5,5-bis(hydroxymethyl)pyrrolidin-2-yl] moiety, as sugar mimic, were synthesized from O,O-cyclohexylidene derivative of 4,4-bis(hydroxymethyl)-4-nitrobutanal in multi-gram scale. The synthetic route consisted of three stages: (i) the synthesis of corresponding derivative of 5,5-bis(hydroxymethyl)pyrrolidine-2-carbonitrile, (ii) the construction of ethyl thiazole-2-carboxylate part by the conversion of the pyrrolidine-2-carbonitrile into the N-trifluoroacetyl derivative followed by cyclocondensation with L-cysteine ethyl ester and then by dehydrogenation, and (iii) the final transformation of the ethyl thiazole-4-carboxylate into the aza-analogues of TZF. The TZF aza-analogues were evaluated for their antiviral activities in cell-culture-based assays.

In this work, two sets of selective laser melting (SLM) process parameters were used alternately to produce a layer-structured NiTi sample. The transformation behavior of the sample shows that austenite transforms gradually into martensite over a wide temperature range (~130K) during cooling. A microstructure composed of alternating layers of austenite and martensite is observed at room temperature. The sample shows excellent damping performance and the Elinvar effect, which originates from the gradual formation of martensite. This work suggests that SLM could serve as an effective way to directly fabricate functionally graded materials.

No abstract is provided for this article.

Purpose The purpose of this paper is to compare different powder metallurgy (PM) processes to produce ceramic parts through additive manufacturing (AM). This creates the potential to rapidly shape ceramic parts with an almost unlimited shape freedom. In this paper, alumina (Al 2 O 3 ) parts are produced, as Al 2 O 3 is currently the most commonly used ceramic material for technical applications. Design/methodology/approach Variants of the following PM route, with indirect selective laser sintering (indirect SLS) as the AM shaping step, are explored to produce ceramic parts: powder synthesis, indirect SLS, binder removal and furnace sintering and alternative densification steps. Findings Freeform-shaped Al 2 O 3 parts with densities up to approximately 90 per cent are obtained. Research limitations/implications The resulting Al 2 O 3 parts contain inter-agglomerate pores. To produce higher-quality ceramic parts through indirect SLS, these pores should be avoided or eliminated. Originality/value The research is innovative in many ways. First, composite powders are produced using different powder production methods, such as temperature-induced phase separation and dispersion polymerization. Second, four different binder materials are investigated: polyamide (nylon-12), polystyrene, polypropylene and a carnauba wax – low-density polyethylene combination. Further, to produce ceramic parts with increased density, the following densification techniques are investigated as additional steps of the PM process: laser remelting, isostatic pressing and infiltration.

Several ribavirin congeners containing a hexitol moiety were prepared via ring opening of two different epoxides with the methylcarboxylate ester of triazole and further elaboration. Unfortunately, none of the newly synthesized compounds displayed appreciable antiviral activity.

Polycationic compounds, i.e. poly-l-lysines and poly-d-lysines, were evaluated for their in vitro effect on the replication of various viruses. Poly-l-lysines of different molecular weight proved inhibitory to the replication of several enveloped viruses, such as human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), respiratory syncytial virus (RSV), influenza A virus, Sindbis virus, Semliki Forest virus, vesicular stomatitis virus (VSV), herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (CMV). The mechanism of action of the polylysines against HIV-1, RSV and CMV could be attributed to an inhibitory effect on virus binding to the host cells, as demonstrated by an indirect immunofluorescence/laser flow cytofluorographic method, virus plaque reduction and measurement of radiolabelled virion association with the cells, respectively.