Peptide drug could treat long COVID, prevent reinfection

A research team led by the QIMR Berghofer Medical Research Institute has developed a new drug that could potentially protect against infection by any SARS-CoV-2 variant and reverse the persistent inflammation that is a major driver of long COVID — a debilitating condition that is thought to affect 10–20% of those infected with COVID-19. That’s according to the second major study demonstrating the preclinical effectiveness of the peptide-based drug, NACE2i, as published in the journal Nature Communications.

The first major study by the research team in 2021 showed the SARS-CoV-2 virus hijacks the ACE2 receptor on the cell’s surface and draws it into the nucleus or control centre of the cell, triggering a process that is essential for the virus to replicate. NACE2i works by reprogramming the hijacked ACE2 receptor, which disarms the virus and stops it replicating. The reprogrammed ACE2 receptor is returned to the cell surface where it acts as a lock that prevents the virus from entering the cell. This process also reverses the inflammation COVID-19 causes in the lungs.

Epigeneticist and co-lead author Professor Sudha Rao, who heads QIMR Berghofer’s Gene Regulation & Translational Medicine group, said the new drug has been tested repeatedly by independent laboratories using a variety of preclinical models.

“The results of this second major study are really exciting,” Rao said. “It shows our drug, NACE2i, stops the virus replicating and protects against reinfection.

“We believe it could be a highly promising adjuvant to boost the effectiveness of existing vaccines, providing long-lasting protection against any variant of the virus that tries to enter the cells.

“The other major discovery is that we uncovered the pathway that the virus uses to induce the persistent inflammation which causes organ damage found in long COVID.

“This study shows our drug prevents that inflammation and even repairs damaged lung tissue in preclinical models. It is both a prevention and a treatment.”

First author and QIMR Berghofer Research Officer Dr Wen Juan Tu said it was very exciting to see NACE2i repairing damaged lung tissue in preclinical models.

“The images are really remarkable,” Tu said. “In the damaged lung, you see it is missing the surface layer of the lung bronchiole area. After treatment with NACE2i, the lung is restored to normal function with a healthy surface layer.”

The researchers have also developed a biomarker blood test to detect the presence of the protective ACE2 receptor layer around cells. They tested this in human blood samples and found it was lacking in patients who had repeated COVID-19 infections. The study found NACE2i restored this biomarker of protection.

Immunologist and co-lead author Professor Nabila Seddiki, Research Director of Immunology & Infectious Diseases Commissariat à l’Energie Atomique (CEA), Paris-Saclay University and INSERM in France, also tested NACE2i in preclinical COVID-19 models.

“When we looked at the results it was very clear the peptides were inhibiting inflammation in our SARS-CoV-2 models, which was really great to see,” Seddiki said.

The next step is to begin clinical trials of NACE2i.

Pictured: High-tech imaging of SARS-CoV-2 infected lung tissue. Image credit: QIMR Berghofer.