Download Development of antiviral drugs for treatment of respiratory syncytial

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.
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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].