Pulmonary permeability oedema is a life-threatening accumulation of fluid in the lungs, due to capillary leak either combined or not with impaired lung fluid clearance. It causes lack of oxygenation of the blood and can occur in patients with the Acute Respiratory Distress Syndrome (ARDS), which is the major complication in patients with severe COVID-19. The accumulation of liquid inside the lung’s airspace is linked to defects in the functioning of the epithelial sodium channel (ENaC), which can be induced by bacterial and viral toxins, including the spike protein of SARS-CoV-2. Pulmonary permeability oedema and lung tissue inflammation significantly contribute to the high mortality rate observed in patients with severe ARDS and severe COVID-19. Both of these medical conditions require invasive mechanical ventilation (IMV) and intensive care treatment.
The solnatide peptide (a.k.a. TIP peptide, AP301) was developed and characterized by Dr. Rudolf Lucas, Medical College of Georgia at Augusta University, USA. The Vienna company APEPTICO, the proprietary owner of solnatide, has been studying the biological function of this molecule for many years. Solnatide is currently being tested in clinical trials for the treatment of patients with moderate to severe ARDS as well with COVID-19.
The three-dimensional structural analysis of solnatide was led by Dr. Maria Macias, ICREA researcher and head of the Structural Characterization of Macromolecular Assemblies lab at IRB Barcelona, in collaboration with the APEPTICO scientific team and built upon earlier findings from Dr. Douglas Eaton’s (Emory) and Dr. Rudolf Lucas’ (Augusta University) research groups. Solnatide was manufactured by BCN Peptides in Barcelona.
Based on the conformational studies and in the analysis of charge distribution of the solnatide peptide surface, which has been published in the Computational and Structural Biotechnology Journal, the collaborators propose a model to describe how the solnatide peptide may interact with the cytoplasmic C-terminal domain of the ENaC-α subunit via electrostatic complementarity.
Commenting on the study, Dr. Bernhard Fischer, CEO of APEPTICO, stated: "In this regard, the work allowed the scientists to detail the mechanism of action of the solnatide peptide and its interaction with the sodium channel ENaC, which is responsible for the removal of pulmonary liquid in life-threatening conditions such as COVID19-associated and non-COVID ARDS”.
Dr. Lucas commented “that the elegant analytical and molecular docking studies from Dr. Macias’ group not only confirmed earlier findings from his research, but actually further elucidated the mechanism of action of solnatide, which is a unique and direct activator of ENaC. In view of the importance of ENaC in both the alveolar and capillary endothelial compartments, this research will foster the development of novel peptide-based therapies for both non-COVID and COVID-ARDS, for which no proven pharmacological treatments exist to date”.
“Our work has focused on describing the structure of the peptide and proposing a mechanism of action to pave the way for possible improvements to its sequence, that is to say, small modifications that can make it more effective” added Dr. Macias.
This study received funding support from the European Commission (EC), Grant No. 101003595 and from the Austrian Research Promotion Agency (FFG), Grant No.880862.
Tzotzos et al. Critical Care (2020) DOI: 10.1186/s13054-020-03240-7 Martin-Malpartida et al. Computational and Structural Biotechnology Journal (2022) DOI: 10.1016/j.csbj.2022.04.031 Lucas et al. Science 263: p814, 1994 Czikora et al. American Journal of Respiratory and Critical Care Medicine (2014) DOI: 10.1164/rccm.201405- 0833OC Lucas et al. Journal of Biological Chemistry (2016) DOI: 10.1074/jbc.M116.718163 Czikora et al. Frontiers in Immunology (2017) DOI: 10.3389/fimmu.2017.00842
APEPTICO Forschung und Entwicklung GmbH (“APEPTICO”) is a privately-held clinical stage biotechnology company with offices in Vienna, Austria, developing peptide-based products targeting life-threatening pulmonary diseases, including oedematous respiratory failure, acute lung injury, primary graft dysfunction, high altitude pulmonary oedema and PHA type 1. APEPTICO makes use of its technology platforms PEPBASE(TM) and PEPSCREEN(TM) to significantly reduce cost and shorten time to market.
APEPTICO’s investigational compound solnatide (INN, laboratory code AP301) is a synthetically manufactured peptide, and was originally designed for the therapeutic treatment of patients with Acute Respiratory Distress Syndrome (ARDS) and various forms of life-threatening pulmonary permeability oedema (PPO). Orally inhaled solnatide IMP has completed a first-in-man (FIM) Phase I clinical study (EUDRACT No. 2011-000223-33), and has delivered clinical proof-of-concept in a randomised, placebo-controlled, double-blinded Phase II clinical study (EUDRACT No. 2012-001863-64) as well as in a Phase II pilot study (EUDRACT No. 2013-000716-21) in patients suffering from pneumonia, sepsis, ARDS, Primary Graft Dysfunction, and other causes of life-threatening pulmonary dysfunction. Currently, solnatide is being tested in a phase IIB clinical study for the treatment of lifethreatening pulmonary permeability (EUDRACT No. 2017-003855-47), and is being used for the treatment of severe COVID-19 patients following infection with the new corona virus (SARS-CoV-2).
Involvement of ARDS in severe cases of COVID-19
ARDS plays a major, if not the major role in the morbidity and mortality in COVID-19 patients. Acute respiratory distress syndrome (ARDS) is characterized by acute lung injury, non-cardiogenic pulmonary oedema and severe hypoxia. Several studies reporting the clinical progression and characteristics in hospitalized COVID-19 patients have focussed on the prevalence of ARDS amongst these patients and particularly amongst the more severe cases. From these studies it is obvious that one fifth to one third of hospitalized COVID-19 patients developed ARDS. One fifth to one third of hospitalized patients suffering from COVID-19 required transfer to the ICU unit. Amongst COVID-19 patients requiring ICU treatment approximately two thirds suffer from life-threatening ARDS. Estimates of the mortality rate amongst COVID-19 ICU patients ranges from 16.7% to 61% (Tzotzos et al. 2020). At present no pharmacological agent has been approved specifically for the therapeutic treatment of ARDS and pulmonary permeability oedema.