Antivirale Therapien

Targeting cellular kinases to develop next-generation broadly-acting antiviral drugs

01.02.2024 bis 30.01.2027

To treat currently circulating viral infectious diseases and to be prepared for pandemic virus outbreaks, it is essential to establish therapeutic options that have a broad efficacy spectrum. Furthermore, such drugs should act against host cell factors to minimize resistance occurrence. In this sense, we propose that kinases, especially ABL, SRC, GAK, AAK1, EGFR, p38 MAPK, and JAK kinases, play key roles in different stages of several viral infections and associated immune responses. This is important since one of the reasons for the high pathogenicity of several viruses is that an exaggerated immune response, the cytokine storm, can often be more harmful to organs than the direct damage inflicted by viral replication. Hence, the main goal of this proposal is to establish broad-spectrum dual-specific inhibitors that have direct antiviral but also anti-inflammatory effects to limit virus-induced cytokine storms and immunopathology. We plan to develop such compounds by exploiting the Tübingen Kinase Inhibitor Collection (TüKIC), a proprietary collection of >12,000 kinase inhibitors. The compounds’ properties will be evaluated in vitro enzymatically and for their antiviral activity (S2/S3 Labs), which will be studied in cellular systems previously established within the consortium. State-of-the-art molecular modelling simulations and virtual screening approaches will complement our efforts to further develop analogues of the initial hits. We intend to develop broad-spectrum antivirals against emerging viruses with zoonotic origin, including Dengue, Zika, Ebola, Respiratory Syncytial, coronaviruses, and Influenza viruses, for which there is an unmet medical need for specific antivirals. The best compounds that possess metabolic stability and display antiviral activity in a cellular system without exhibiting cytotoxicity will be evaluated for further pharmacokinetic properties (PK). Developed new tool compounds will be evaluated in collaboration with partners in vivo studies in different models (e.g., animal modes).