Publications

Dextran sulphate inhibits the replication of enveloped viruses (such as retro-, herpes-, toga, arena-, rhabdo-, orthomyxo- and paramyxoviruses), but is inactive against non-enveloped viruses (such as polio, Coxsackie and reovirus). Within the molecular weight (MW) range of 10000–50000, not much variation was observed in the antiviral potencies of different dextran sulphate (DS) samples, irrespective of the virus examined. However, in contrast with the higher MW samples, the low MW DS sample (prepared from dextran with a MW of 1000) was virtually inactive against herpes simplex virus type 1 and type 2, vesicular stomatitis virus, vaccinia virus, influenza A virus, respiratory syncytial virus and togaviruses (Sindbis, Semliki Forest). It was 10–20-fold less active than the higher MW samples against cytomegalovirus and arenaviruses (Junin, Tacaribe). The inhibitory potency of the 1000 MW DS sample against human immunodeficiency virus (HIV) varied considerably depending on the virus strain and cell type. When examined in MT-4 cells, the 1000 MW DS sample was 7000-, 1000-, 200- or 10-fold more inhibitory to HIV-1 HE than HIV-2 EHO , HTLV-III B , HTLV-III RF and LAV-2 ROD , respectively. In CEM cells, however, HIV-1 HE was less sensitive to the inhibitory effect of the 1000 MW DS sample than HIV-2 EHO , equally sensitive as HTLV-III B and fivefold more sensitive than LAV-2 ROD .

The life cycle of HIV-1 requires extensive assistance from the host cell proteins and pathways. TSG101 is one of the cellular proteins involved in the budding process of HIV-1, and plays an important role in the cellular vacuolar protein sorting (Vps) pathway. Its main function being recognizing ubiquitinated cargo, TSG101 also proved to be essential for the budding process of HIV-1 virions. In this process, TSG101 is recruited from internal site of the infected cell to the budding site to aid in the release of the HIV-1 virus particles. Depletion of TSG101 from virus-producing cells can lead to a budding defect. Therefore, TSG101 is a potentially new attractive target for therapeutic intervention in AIDS. This review describes the structure and function of TSG101 and latest progress in the discovery of TSG101-directed HIV-1 inhibitors.

The synthesis and antiviral activity of original dibromoimidazo[1,2-a]pyridines bearing a thioether side chain are reported. Molecular modeling was used to identify biophoric structural patterns that are common to 16 compounds. Structure-activity relationship (SAR) studies identified hydrophobicity (logP) as the most important factor for activity. From these SAR studies, the antiviral activity could be predicted.

Laser Powder Bed Fusion (LPBF) is an additive manufacturing (AM) technique associated with large thermal gradients and thermal strains resulting from the inherent nature of the process. Due to the non-equilibrium solidification conditions, certain alloys suffer from thermally induced micro-cracking, which hinders their exploitation. In this paper, we propose a novel approach towards the processing of a defect-free nickel-based superalloy, Hastelloy X, by means of Laser Powder Bed Fusion (LPBF). A combined experimental and numerical approach was used in order to evaluate the influence of the laser beam intensity distribution and melt track overlap on the temperature evolution, solidification behavior and crack formation. The use of a laser beam with narrow diameter and Gaussian beam intensity distribution leads to keyhole mode melting and a steep cooling rate, whereas a large diameter beam with top-hat intensity distribution leads to the formation of wide and shallow conduction mode melt pools, with a lower cooling rate and consequently a coarser sub-grain microstructure. The decrease of hatch spacing did not show a significant change in the local thermal history within a melt pool when a Gaussian beam was used. On the other hand, with the laser with the top-hat beam profile was used, an overall increase in the temperature of the layer and significantly lower cooling rates were observed. As a result, by decreasing the hatch spacing to 125 µm, micro-crack free Hastelloy X material was produced by LPBF for the first time, using a commercially available powder, simply by optimizing the scanning strategy and without modification of the chemical composition of the alloy. The material in the as-build condition exhibited a higher yield tensile strength (500 ± 17 MPa) than conventionally produced Hastelloy X (340 MPa), with elongation of 31.5 ± 3.0%.

A series of 3'-deoxy-3'-fluoro- and 2'-azido-2',3'-dideoxy-3'-fluoro-D-ribofuranosides of natural heterocyclic bases have been synthesized with the use of universal carbohydrate precursors, viz., 1-O-acetyl-2,5-di-O-benzoyl-3-deoxy-3-fluoro-D-ribofuranose and methyl 2-azido-5-O-benzoyl-2,3-dideoxy-3-fluoro-beta-D-ribofuranoside, respectively. The cytostatic and antiviral activity of the compounds was evaluated against a variety of tumor cell lines and DNA/RNA viruses, respectively. As the most active compound, from both a cytostatic and antiviral activity viewpoint, emerged 3'-deoxy-3'-fluoroadenosine. It inhibited the proliferation of some tumor cell lines (i.e. murine leukemia L1210 and human T-lymphocyte MT-4) at a concentration of 0.2-2 micrograms/mL, and proved inhibitory to the replication of positive-stranded RNA viruses (i.e. polio, Coxsackie, Sindbis, Semliki forest), double-stranded RNA viruses (i.e. reo), and some DNA viruses (i.e. vaccinia) at a concentration of 1-4 micrograms/mL, which is well below the cytotoxicity threshold (40 micrograms/mL).

Camelpox virus (CMLV) is the closest known virus to variola virus. Here we report on the anti-CMLV activities of several acyclic nucleoside phosphonates (ANPs) related to cidofovir [(S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine (HPMPC; Vistide)] against two CMLV strains, CML1 and CML14. Cytopathic effect (CPE) reduction assays performed with human embryonic lung fibroblast monolayers revealed the selectivities of the first two classes of ANPs (cHPMPA, HPMPDAP, and HPMPO-DAPy) and of the hexadecyloxyethyl ester of 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine (HDE-cHPMP-5-azaC), belonging to the newly synthesized ANPs, which are HPMP derivatives containing a 5-azacytosine moiety. The inhibitory activities of ANPs against both strains were also confirmed with primary human keratinocyte (PHK) monolayers, despite the higher toxicity of those molecules on growing PHKs. Virus yield assays confirmed the anti-CML1 and anti-CML14 efficacies of the compounds selected for the highest potencies in CPE reduction experiments. Ex vivo studies were performed with a 3-dimensional model of human skin, i.e., organotypic epithelial raft cultures of PHKs. It was ascertained by histological evaluation, as well as by virus yield assays, that CMLV replicated in the human skin equivalent. HPMPC and the newly synthesized ANPs proved to be effective at protecting the epithelial cells against CMLV-induced CPE. Moreover, in contrast to the toxicity on PHK monolayers, signs of toxicity in the differentiated epithelium were seen only at high ANP concentrations. Our results demonstrate that compounds belonging to the newly synthesized ANPs, in addition to cidofovir, represent promising candidates for the treatment of poxvirus infections.

This work demonstrates a successful in situ method capable of producing an ultra-strong novel Ti composite without aluminium and vanadium. In this method, selective laser melting is used to conduct in situ alloying and reinforcing of a Ti/10.5 wt% Mo 2 C powder mixture. It is shown that this leads to a metastable β-Ti matrix homogeneously reinforced by high aspect ratio, 50–200 nm wide and up to several micrometre long TiC whiskers. The transformations of the phases are controlled by decomposition, dissolution, diffusion, and reformation of constituents. The whisker morphology of in situ formed TiC particles is associated with directional crystal growth along the TiC <110> direction. The developed TiC reinforced β-Ti alloy combines a hardness over 500 HV, a Young’s modulus of 126 GPa, and an ultimate compressive strength of 1642 MPa. Improving the ductility of this composite is the subject of another work.