Clinical development of the solnatide peptide for the treatment of ARDS and COVID-19 during the corona pandemics. Identification of the 3D conformational ensemble of solnatide by crystallography and NMR
Bernhard Fischer
CEO, APEPTICO
Solnatide is a 17-residue synthetic peptide and has been designed on the lectin-like domain of TNF-alpha. Various derivatives of solnatide have been proposed and chemically synthesized. Solnatide peptide is stabilized by extra intra-molecular disulfide bonds. Solnatide peptides demonstrated to activate ENaC in several experimental models of lung oedema, ischemia reperfusion injury (IRI), high altitude pulmonary oedema (HAPE), pseudohypoaldosteronism (PHA), acute respiratory distress syndrome (ARDS) and primary graft dysfunction (PGD) following lung transplantation. Today, solnatide is manufactured by solid-phase chemistry at kg-scale for the structural & molecular characterisation, as well clinical development and specification settings.
Solnatide is administered as a peptide-aerosol directly into the pulmonary airspace of patients with severe lung dysfunction.
In 2021 and 2022 during the new coronavirus pandemic, solnatide has been applied for the therapeutic treatment of both patients with moderate-severe ARDS and mechanically ventilated COVID-19 patients in clinical studies as well within national compassionate use programs.
We compare basic characteristics of ARDS patients vs. COVID-19 patients, discuss limitation in hospital management during the pandemics, as well present preliminary clinical outcome data.
We also report the molecular structure and interaction between solnatide and the pulmonary ENaC channel based on the conformational ensemble displayed by the peptide as generated through the combination of the crystallography and NMR. Analysis of the conformational ensembles displayed by solnatide shows that the peptide recaptulates structural features previously identified as relevant for the ENaC-activating effect of the lectine-like domain of TNF, namely the critical role of a triad of residues in solnatide, a hydrophobic region comprising thress consecutive residues, and the presence of a charged dipol. The middle region of solnatide, is ordered, shows H-bonding capacity, and adopts a backbone confirmation similar to that of the native protein.
The structural coordinates of solnatide will be uploaded to the PDB Protein Data Bank.
Professor Dr. Bernhard Fischer is a biotechnology expert and entrepreneurial pharma manager with long standing record in international life science biotechnology and pharmaceutical companies. In the course of his career he headed senior management positions in biopharmaceutical research and development, regulatory affairs, chemistry manufacturing & controls documentation and technical drug development.
In the course of his career he headed senior management positions in biopharmaceutical research and development, regulatory affairs, chemistry manufacturing & controls documentation and technical drug development. During his professional development he was research biochemist at the Institute of Molecular Biology and Institute of Biotechnology in Germany, Higher Scientific Officer at the Department of Protein Engineering of the AFRC in the United Kingdom, Head of the Department of Recombinant Proteins at the Biomedical Research Center of Baxter in Austria, Manager Chemistry Manufacturing & Controls and Manager Regulatory Affairs at Sandoz (Novartis) in Austria, Chief Technical Officer at Avidis in France, Vice President Development and Chief Technical Officer at Fibrex Medical in Austria.
Currently, Dr. Fischer serves as founder and CEO of APEPTICO a biotechnology start-up company developing protein and peptide based drugs.
Dr. Fischer is Lecturer for Protein Chemistry and Biomedicinal Drug Development and Regulatory Affairs at various Universities and Business Schools.