Development of enhanced furin inhibitors with reduced toxicity as potential broad spectrum antiviral drugs

At the beginning of the twentieth century, the focus of peptide research was largely on human signalling hormones. A breakthrough in the field of peptide therapeutics was the first medicinal application of insulin isolated from animal pancreas, which revolutionized the treatment of type 1 diabetes. Since then, more than 80 peptide drugs have been used for a variety of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection, and chronic pain. The production of synthetic therapeutic peptides has become possible with the development of solid-phase peptide synthesis by Merrifield in the year 1963. This milestone has provided access to pure and sufficient amounts of peptides enabling countless research projects to determine the functional and structural bioactive properties of peptides. In the context of drug discovery, this thesis focused on the development of synthetic inhibitors of the Ca2+-dependent type-I transmembrane protein furin, which belongs to the proprotein convertase (PC) family of serine endoproteases. It is ubiquitously expressed in vertebrates and invertebrates and activates a large number of proprotein substrates in the secretory pathway, including prohormones, proenzymes, and proforms of receptors or extracellular matrix proteins. Furin also plays a crucial role in tumorigenesis, neurodegenerative disorders, and diabetes or arteriosclerosis as well as in many bacterial and viral diseases. It cleaves numerous precursors of bacterial toxins such as Pseudomonas exotoxin A, Shiga-, and diphtheria toxin. Some enveloped viruses possess surface proteins that contribute to the fusion between viral and host cell membranes and have to be activated by furin or related PCs. Examples of such glycoproteins include those from highly pathogenic avian Influenza viruses, Measles, Ebola, and Flaviviruses such as Dengue-, West Nile-, and Zika-virus. Recent studies revealed that furin is implicated in the activation of the spike (S) protein of the new SARS-CoV-2. Given its implications in ...