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Searching for novel candidate antiviral drugs and their preclinical evaluation

Research group
Active research
Project owner
Institute of Biomedicine

Short description

Our research focuses on searching for novel candidate antiviral drugs and their evaluation at preclinical level. This goal is accomplished through screening for antiviral activity in cultured cells of libraries of random and drug-like compounds, medicinal plant extracts, and natural products. We focus on human respiratory viruses for which no effective and non-toxic antiviral drug has been approved. Our research resulted in several candidate antiviral compounds against respiratory syncytial virus and coronavirus 229E.

We search for novel candidate antiviral drugs targeting pathogens that cause acute infections of airways such as respiratory syncytial virus (RSV), human metapneumovirus, rhinoviruses, some coronaviruses, and some parainfluenza viruses. Respiratory viruses are highly contagious and tend to cause severe disease in infants, elderly, and immunocompromised individuals of any age. Remarkably, most of humans experience virus-induced discomfort of the airways at least once a year, yet except for influenza virus no antiviral drug is available to ease respiratory disease. More importantly, due to high contagiousness, emergence of either novel human respiratory viruses or new viral variants of existing pathogens must be considered as potential pandemic-triggering event. Hence, development of specific antivirals targeting particular respiratory virus or broad-spectrum antivirals against viral families where respiratory pathogens are classified is urgently needed.

To search for novel candidate antivirals we have been screening large (up to 20 000) collections of random or drug-like compounds, extracts from medicinal plants, metabolites, and other natural products for antiviral activities in cultured cells. Compound that protected the cells against infection with particular respiratory virus (“hit”) is subjected to chemical optimization to figure out whether any modification of the “hit” structure would improve its antiviral activity. The resulting “lead” compound is then tested for efficacy and safety in the human airway epithelium-mimicking cultures of cells and in laboratory animals. An important part of antiviral studies is an elucidation of the mode of antiviral activity of “lead” compounds. Here we ask whether the “lead” compound targets the virus or the cell. If virus, which stage of the virus life cycle is affected? If cell, which signaling pathways is involved? We then passage the virus in cells in the presence of “lead” compound to select for the resistant viral variants to identify the virus component involved in the “lead” activity. 

To date our antiviral research has resulted in several candidate antiviral compounds. These include two novel anti-RSV compounds P13 and C15 which inhibited the fusogenic activity of the viral F protein required for the virus entry into cells. The F protein occurs as a trimer stabilized by association between hydrophobic phenylalanine residues and balanced by a ring of negatively charged amino acids (Fig. A), and compound C15 targeted negatively charged aspartic acid residue in this balancing structure thus inhibiting the virus entry into the cells. Another anti-RSV compound PG545 targeted the glycosaminoglycan binding component of the virus leading to the disruption of viral particles. Joanna Said, a post-doc in our group has found that the virus-particle disrupting activity of PG545 was also evident in another glycosaminoglycan-binding pathogen herpes simplex virus (Fig. B). Anna Lundin, a former PhD student and post-doc in our group has identified compound K22 which appeared to target the coronavirus 229E protein nsp6 involved in formation of the virus-induced intracytoplasmic net of double-membrane vesicles, a structure known as part of the virus replication center (Fig. C). Jackson Mollel, a PhD student in our group, has found anti-RSV activities in extract of five medicinal plants from Tanzania.  

Antiviral screening frequently results in identification of inhibitors of various components of cellular pathways that are involved in modulation of viral infection of cells. We have found that inhibitors of epidermal growth factor receptor tyrosine kinase activity affected the syncytium-forming activity and RSV spread in cells.   

Image
Fig. (A) Compound C15 destabilizes trimer structure of F protein of RSV. (B) Compound PG454 disrupts HSV particles (Said et al., Antimicrob. Agents Chemother. 2014). (C) Compound K22 inhibits coronavirus-induced structures in cells (for details see text).
Edward Trybala, group leader

edward.trybala@microbio.gu.se

Group members

Edward Trybala

Tomas Bergström

Joanna Said

Charles Hannoun

Jackson Mollel

Colores Uwamariya