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Research Project Edward Trybala; Department of Clinical Virology Novel antiviral drugs for treatment of viral respiratory infections in humans and their mechanisms of action No vaccine or an effective antiviral drug is currently available for prevention/treatment of acute respiratory infections in humans caused by respiratory syncytial virus (RSV), coronaviruses (CoV) or rhinoviruses (RhV). These viruses invade ciliated cells of human airways causing pandemic infections (CoV-SARS), severe disease in infants (RSV) or respiratory discomfort known as common cold (RhV). Many events of the infectious cell cycle mechanism of these viruses are poorly understood. The aim of this project is to search for and to evaluate candidate anti-RSV, -CoV or -RhV drugs. An initial phase of the project, based on the screening for possible antiviral activity of large collections (libraries) of random, custom-synthesized, and natural compounds identified 2 anti-CoV and 7 anti-RSV hit compounds. Subsequent development of identified hit compounds includes: (i) Optimization through chemical synthesis of a number of “hit” analogues and their testing for improved antiviral properties and possible low cytotoxicity. This part of the project is carried out in cooperation with Nina Kann (Chalmers). (ii) Evaluation of optimized “hit” compound for efficacy and safety in cultures of cells mimicking ciliated epithelium of human respiratory tract, and in experimental animals, and (iii) elucidation of the mechanism of antiviral activity of candidate compounds. The latter task would require identification of a step of the virus infectious cell cycle affected by candidate drugs, i.e., recognition of which viral component is targeted by a drug, what is a biological function of this viral constituent, and which cellular ligand it interacts with. Preparation of the drug-resistant variants of CoV and RSV and identification of specific gene alterations in these mutant viruses is/will be performed, in parallel with other experimental approaches, to fulfill this task. The proposed project, apart from its significance for antiviral research, may help to extend our knowledge on biological functions of viral components and their cellular receptors. The project has already resulted in several promising anti-RSV and anti-CoV compounds. 1. 2. 3. 4. Members of research group Edward Trybala, PhD., DVM. Docent Beata Adamiak, Ph.D. Post-doctoral research position. Anna Lundin, MSc. PhD student. Ann-Sofia Tylö, Biomedical analyst. Relevant publications 1. Bergefall K, Trybala E, Johansson M, Uyama T, Naito S, Yamada S, Kitagawa H, Sugahara K, Bergstrom T. (2005): Chondroitin sulfate characterized by the E-disaccharide unit is a potent inhibitor of herpes simplex virus infectivity and provides the virus binding sites on gro2C cells. J. Biol. Chem. 280:32193-32199. 2. Ekblad M, Bergström T, Banwell MG, Bonnet M, Renner J, Ferro V, Trybala E. (2006): Anti herpes simplex virus activities of two novel disulfated cyclitols. Antivir. Chem. Chemother. 17:97-106.* 3. Uyama T, Ishida M, Izumikawa T, Trybala E, Tufaro F, Bergström T, Sugahara K, Kitagawa H. Chondroitin 4-O-sulfotransferase-1 regulates E disaccharide expression of chondroitin sulfate required for herpes simplex virus infectivity (2006). J. Biol. Chem. 281:38668-38674. 4. Ekblad M., Adamiak B, Bergefall K, Nenonen H, Roth A, Bergstrom T, Ferro V, Trybala E. (2007). Molecular basis for resistance of herpes simplex virus type 1 mutants to the sulfated oligosaccharide inhibitor PI-88. Virology. 367:244252. 5. Adamiak B, Ekblad M, Bergstrom T, Ferro V, Trybala E. (2007). Herpes simplex virus type 2 glycoprotein G is targeted by the sulfated oligo- and polysaccharide inhibitors of the virus attachment to cells. J. Virol. 81:1342413434. 6. Adamiak B, Trybala E, Mardberg K, Johansson M, Liljeqvist JA, Olofsson S, Grabowska A, Bienkowska-Szewczyk K, Szewczyk B, Bergstrom T (2010). Human antibodies to herpes simplex virus type 1 glycoprotein C are neutralizing and target the heparan sulfate-binding domain. Virology. Feb 20. [Epub ahead of print]. 7. Ekblad M, Adamiak B, Bergstrom T, Johnstone KD, Karoli T, Liu L, Ferro V, Trybala E (2010). A highly lipophilic sulfated tetrasaccharide glycoside related to muparfostat (PI-88) exhibits virucidal activity against herpes simplex virus. Antiviral Res. Feb 19. [Epub ahead of print].