A research platform for the pre-clinical development of future peptide drug candidates

Todays drug research community is showing increasing interest in bioactive peptides as a potential starting point for the development of innovative therapies. Peptide entities promise very high affinity to their target receptor and are more selectivity than small molecule drugs. Moreover, peptide therapeutics are less toxic due to their rapid clearance. Unfortunately, many promising peptide drug candidates never make it to the clinics because of the translational challenges of transforming a lead into a clinical candidate. Because it is not realistic for a single laboratory or scientist to perform multidisciplinary peptide drug research alone, only closely-connected interdisciplinary teams successfully work in preclinical peptide research. In our project, we postulate PeptAIDes (Peptides for the treatment of Autoimmune and Inflammatory Diseases), a highly collaborative research platform including the entire spectrum of disciplines in drug development, which will transform therapeutic leads into clinical candidates. PeptAIDes will combine four pillars in one collaborative approach: i) molecular studies of the peptide-receptor interaction, ii) peptide chemistry to implement specialized peptide synthesis strategies for optimization of the candidate properties, iii) pharmacological evaluation to enable the development of drug-like features and iv) validation of candidates in relevant models of autoimmune and inflammatory diseases. The young independent investigator research group consists of Roland Hellinger (Pharmacologist, project coordinator), Kirtikumar B. Jadhav (Synthetic chemist), Eva-Maria Zangerl-Plessl (Computational chemist), Dagmar Gotthardt (Immunologist) and Tim Hendrikx (Molecular biologist). The consortium has the strong support of the Medical University of Vienna, the University of Vienna and the University of Veterinary Medicine Vienna. PeptAIDes will serve as an innovative hub for interdisciplinary cooperation in pre-clinical development of peptide therapeutics. By providing proof of concept for candidates, we will take the first step in translating academic research to the clinical stage of drug development.

Over the past five years, the interdisciplinary Young Independent Researcher Group PeptAIDes has worked on fundamental questions in peptide science and the molecular and cellular mechanisms driving inflammatory or autoimmune diseases and cancer. Overall, the implications of this project span inflammatory and autoimmune disorders, metabolic diseases, cancer, renal injury, and pain management. We showed that natural peptides are promising molecules with drug-like properties and have implemented technologies to use them as bioactive probes or molecular scaffolds to prepare new bioactive molecules. We studied new approaches for computationally aided rational peptide design and implemented new peptide library synthesis approaches. We refined the molecular grafting approach using scaffold matching and structural model prediction workflows. Proof-of-concept data were established for new peptide therapeutics that alter immune cell transendothelial migration or peptide shuttle systems that enable the transport of therapeutic cargoes into the central nervous system. Other achievements include the characterization of novel therapeutic peptides that stimulate natural killer cells for cell cytotoxicity against cancerous target cells. In addition, we established a patient-relevant NK cell leukemia model that is being used for functional drug screening. The role of anti-malonaldehyde IgM antibodies in alcohol-related fatty liver disease was investigated, providing new insights into disease development and progression. We developed and patented an 'AI-designed peptide-small molecule conjugate drug-discovery workflow' for the -opioid receptor, opening a promising avenue for non-addictive pain therapies. In summary, the implemented collaborative interdisciplinary strategy demonstrated how cutting-edge peptide science can be translated into meaningful preclinical research and applications in translational medicine while providing tools and workflows that empower the broader research community. Further studies will consider the safety and efficacy of the prepared probes to validate their application in a therapeutic setting.