Systems Biological \(In-Silico\)-Modelling in Infections Diseases for Protein and Peptide-Based Drug-Design, -Discovery and -Development

Infection biology is crucial for addressing global health challenges posed by infectious diseases, which significantly contribute to morbidity and mortality worldwide. For instance, antibiotic resistance accounts for approximately 1.27 million deaths annually, while sepsis causes nearly 11 million deaths each year, representing about 20% of all global fatalities. Fungal pathogens such as Aspergillus fumigatus lead to severe infections, particularly in immunocompromised individuals, with high mortality rates. Additionally, malaria, a parasitic infection, results in over 600,000 deaths annually, primarily affecting children under five. Tuberculosis, another major infectious disease, caused 1.5 million deaths in 2021, underscoring the persistent threat it poses globally. Addressing these challenges requires a deep understanding of the molecular mechanisms underlying infection biology. In my thesis, I adopt a systems biology approach to study the infection process, evaluating both host and pathogen interactions, identifying potential drug targets, and exploring pathophysiology. The focus is on proteins and peptides, starts from structure analysis, docking and molecular dynamics and involves also drug design, discovery, and development for treatment in infectious diseases. This approach enables innovative therapeutic strategies. During my PhD, I worked on five distinct projects: The first project focuses on the retinoic acid receptor alpha (RARα), a nuclear receptor protein involved in immune regulation and infection processes, including tuberculosis. Using virtual screening and drug discovery tools, I identified a novel agonist for RARα, presenting it as a potential activator for this receptor (published as first author in PLOS ONE). The second project examines the virulence factor DHN melanin from Aspergillus fumigatus and its interaction with human cells. By analyzing evolutionary conservation, compartmental information, and predicted functions and structures, we identified several top targets. Molecular dynamics simulations evaluated binding properties, and high-scoring targets include the experimentally confirmed MelLec receptor and serine protease D, along with newly predicted targets like metalloprotease P2 and aromatic hydrogen receptor (submitted to microLife, shared first author manuscript). The third project, in collaboration with medical doctors, investigates the interaction between vascular endothelial cadherin (VE-cadherin) and vascular endothelial protein tyrosine phosphatase (VE-PTP) proteins in sepsis infection, revealing how soluble VE-cadherin (SVE-cadherin) disrupts endothelial barrier integrity (published as co-author in iScience). The fourth project focuses on the lysyl-tRNA synthetase (PfKRS1) protein as a promising target for antimalarial drug development. I identified the best small molecule candidate for this purpose. In the fifth project, I explored how Cathelicidin peptides from four different organisms disrupt bacterial and fungal model membranes, addressing both bacterial antibiotic resistance and antifungal development (first author publication in preparation). In conclusion, I elucidate in five own projects, how specific proteins and peptides are key players in infection biology, functioning as virulence factors, antimicrobial targets, and mediators of immune responses.