Molecular model of a coronavirus spike protein (red) bound to an angiotensin-converting enzyme 2 (ACE2) receptor (blue) on a human cell. Credit: Juan Gaertner/Science Photo Library/Getty Images.
The scientists used an automated process called SELEX (Systematic evolution of ligands by exponential enrichment), where they created a library of 1,000 billion short DNA sequences, randomly generated, and then exposed them to the key amino acid chains found in the human and mouse version of ACE2. “We found two molecules that bind to a specific region of the receptor, close to the spike-ACE2 interaction domain”, says author, Paolo Ciana, Professor of Pharmaceutical Biotechnologies at Università di Milano. “These molecules are short strands of DNA, and in vitro they effectively prevent the access of SARS-CoV-2 spike through ACE2.”
The researchers aim to develop a new drug, for which they have already filed a patent request. “It would prevent the spreading of the virus from the original infection site, and the onset of severe disease in infected people”, says Vincenzo Lionetti, Associate Professor of Anesthesiology at Sant’Anna School of Advanced Studies in Pisa. “It could help to circumvent the issue of resistant SARS-CoV-2 variants, because the viral entry in the host cell is a complex multistep process and it is unlikely that a single mutation on spike protein could be sufficient to move the whole mechanism on to another domain of the ACE2,” says author, Angelo Reggiani, senior scientist for Drug Discovery at Istituto Italiano di Tecnologia in Genoa.
The next steps will be to stabilise the two molecules and to study their behaviour in animal models, to shed light on their possible interference with the normal activity of ACE2, an important enzyme for the cardiovascular system. “Blocking the enzymatic function of the receptor, in particular the production of angiotensin 1-7, is potentially associated with inflammation, increased coagulation and increased blood pressure”, says cardiologist Paolo Verdecchia, former Director of Medicine at the Hospital of Assisi, who is not involved in this research.
The site of interaction with the spike protein is different from the enzymatic domain on ACE2, so the authors believe the binding of the candidate drug to the receptor shouldn’t influence its enzymatic activity. “If a clinical trial can show these molecules are effective and well tolerated, it would be a great progress,” concludes Verdecchia.
