NICE, France _ Viruses have evolved many intricate ways to infectmammalian and other types of cells. One group of researchers reportedon their attempts to mimic how a virus naturally enters a cell to deliverits genetic material or invade the host. Ernst Wagner and coworkers atthe Research Institute of Molecular Pathology and at Bender & Co. inVienna, Austria, have tried to imitate the natural transport mechanismof nucleic acids into cells to develop a synthetic version of the genetransfer system.Wagner and colleagues used the transferrin receptor-medicatedendocytosis mechanism of an adenovirus as a model for incorporatingendosome-disruptive peptides into DNA complexes. Viruses haveacquired special mechanisms to release their genome from endosomesinto their hosts cytoplasm, Wagner told attendees at the gene therapysession of the 21st International Symposium on Controlled Release ofBioactive Materials here.The Austrian researchers found certain viral peptides disrupt naturalmembranes when linked to polylysine, which acts as a ligand forreceptor-mediated endocytisis. They replaced the whole virus withsmall synthetic peptides similar to sequences in the hemagglutinin ofthe influenza virus or in the VP-1 protein of rhinovirus. At neutral pH,the peptides remained inactive and disordered, When acidified atendosomal pH, these proteins formed an amphipathic helix thatinteracted with the lipid membrane of the cell, destabilizing themembrane. The synthetic virus-like peptide system disruptedliposomes; erythrocytes and endosomal membranes.In vivo vectors may require different optimization steps than the exvivo vectors," Wagner said. "There is the hope that these syntheticvirus-like vectors will be useful but not in the current version we dealwith." At present, they are evaluating this system as an alternative tousing adenovirus complexes for gene transfer."Wagner has told us that these synthetic virus-like gene deliverysystems are not ready for prime time," said Frank Szoka Jr., of theUniversity of California, San Francisco, and co-chair of the genetherapy session. "That is, they are not ready for in vivo testing yet. ButWagner and his group have shown that with relatively simple systems_ although still using an inactivated adenovirus _ that they can getgene transvection."Szoka, whose work has focused on liposomes and liposomic mimeticsystems as gene delivery systems, added that "The more excitingresults with peptide synthetic virus-like systems are not yet as effectiveas adenovirus systems for gene therapy. [Wagner and colleagues] arelooking at some type of hybrid system, using both the peptide syntheticsystem and an adenovirus. You get some of the benefit of having avirus there but eliminate some of the problems that come withadenovirus transvection. The peptide is a short enough molecule to getaway from some of the immunological problems, such asinflammation, that accompany adenovirus administration." n

-- M. J. Pramik Special to BioWorld Today

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