Preventing cellular hijacking: Study pinpoints potential pathway to new therapeutic approaches for COVID-19
They have discovered that the virus might hijack certain cellular processes; this data showing molecular links may help scientists identify drugs that are highly effective in blocking the virus, said the authors, based at EMBL Heidelberg, the Universidad Nacional de San Martín in Buenos Aires, Merck KGaA Darmstadt, and University College Dublin (UCD).
Their study was published in Science Signaling.
Hijacking cellular processes
Early on in the COVID-19 pandemic, it was established that SARS-CoV-2 infects cells by binding to the human protein ACE2, which plays a role in regulating blood pressure, said the team.
But ACE2 is almost absent in human lung cells, so they questioned why the lungs then were one of the most affected organs in COVID-19. The researchers had an idea that ACE2 might be more than a blood pressure regulator and may not be the only actor in the SARS-CoV-2 infection mechanism.
EMBL’s Gibson team, in collaboration with Lucía Chemes at Universidad Nacional de San Martín in Buenos Aires and partners from Merck Darmstadt and UCD, analyzed sequences of ACE2 and other human proteins involved in SARS-CoV-2 infection, such as a class of proteins called integrins. They focused on short strings of amino acids called short linear motifs (SLiMs), which are involved in transmitting information between the inside and outside of cells.
They saw that ACE2 and several integrins contain SLiMs that are probably involved in endocytosis and autophagy – cellular processes of uptake and disposal of substances, respectively. This result suggests previously unknown roles of ACE2 and integrins in cell physiology. “If SARS-CoV-2 targets proteins involved in endocytosis and autophagy, it means these processes might be hijacked by the virus during infection,” said Bálint Mészáros, a postdoc in the Gibson team and lead author.
Several of the research group’s findings were experimentally verified by Ylva Ivarsson and her group at Uppsala University in Sweden, confirming the predicted protein interactions, and that these interactions are regulated by the naturally occurring addition of ions containing phosphorus.
Potential treatments for COVID-19
Their findings might lead to new therapeutic approaches for COVID-19. “SLiMs could ‘switch’ to turn viral entry signals on or off. This means that if we can find a way to reverse these switches using drugs, this might stop coronavirus from entering cells,” said Chemes.
Together with a collaborator from Merck Darmstadt, the team identified several candidate drugs that could interfere with SLiM-induced endocytosis or autophagy, such as cilengitide, a selective integrin inhibitor, may be useful in blocking virus attachment to target cells, but also in RGD-dependent binding of pathogens that protects against sepsis.
The antibody abituzumab (DI-17E6) is a pan-α integrin antibody that has been shown to have potential for blocking virus entry. Furthermore, integrin inhibitor, GSK3008348, has been shown to have an effect on lung fibrosis in a mouse therapeutic model.
“If clinical trials prove some of these drugs to work against COVID-19, this could be a game changer,” said Manjeet Kumar, a bioinformatics scientist in the Gibson team and a senior author in the study.
