Protein sequences provide clues as to how SARS-CoV-2 infects cells
Researchers at EMBL Heidelberg have identified sequences in human proteins that could potentially be used by EARS-CoV-2 to infect cells. They have discovered that the virus can hijack certain cellular processes, and they are discussing possible appropriate drugs for treatment. COVID-19.
In the early days of 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. But ACE2 is almost absent in human lung cells, so how can the lungs be one of the organs most affected in COVID-19? This has given researchers a hint that ACE2 may be more than just a blood pressure regulator, and may not be the only player in the SARS-CoV-2 infection mechanism.
EMBL’s Gibson team, in collaboration with Lucía Chemes at the Universidad Nacional de San Martín in Buenos Aires and partners of Merck KGaA Darmstadt and University College Dublin, has series of ACE2 and other human proteins involved in SARS-CoV-2- infection, as a class analyzes. proteins called integrins. They focused on short strings of amino acid are called short linear motifs (SLiMs), which are involved in transmitting information between the inside and outside of the cells. Rapid identification and comparison of SLiMs was possible thanks to the Eukaryotic Linear Motif (ELM) source, the largest composite SLiM database, which the team and collaborators have been developing for 20 years.
They have seen that ACE2 and several integral SLiMs are likely to be involved in endocytosis and autophagy – cellular processes of uptake and disposal of substances, respectively. This result indicates previously unknown roles of ACE2 and integrins in self-physiology. “If SARS-CoV-2 targets proteins involved in endocytosis and autophagy, it means that these processes can be hijacked by the virus during infection,” said Bálint Mészáros, a postdoctoral fellow in the Gibson team and first author of the study.
Several findings were experimentally confirmed by Ylva Ivarsson and her group at Uppsala University in Sweden. They confirmed the predicted protein interactions and confirmed that these interactions are regulated by the natural addition of ions containing phosphorus. ‘Ylva Ivarsson was the best person we knew to test these predictions. We were delighted that she agreed to join this project, ‘says EMBL leader Toby Gibson. Ylva Ivarsson is equally enthusiastic. “Switching our work to SARS-CoV-2-related research has helped us keep the spirit in the laboratory during the pandemic,” she adds.
Potential drugs for COVID-19
The findings may lead to new therapeutic approaches for COVID-19. ‘SLiMs can’ switch ‘to turn viral access signals on or off. This means that if we can find a way to switch these switches using drugs, it can prevent coronavirus from invading cells, ‘says senior author Lucía Chemes.
Together with a collaborator from Merck KGaA Darmstadt, the team compiled a list of existing drugs that interfere with endocytosis and autophagy. The list contains some surprising candidates, such as the antipsychotic chlorpromazine. “If clinical trials prove that some of these drugs work against COVID-19, it could be a game changer,” said Manjeet Kumar, a bioinformatics scientist in the Gibson team and a senior author in the study.
Highlights, challenges and cooperation during the pandemic
This research was started at the beginning of the first exclusion in Germany in the spring of 2020. The project was an opportunity to strengthen the relations between scientists across the continents. ‘Toby and I have been collaborating since 2012, when Argentina became a fellow member of EMBL. Our previous experience has enabled us to work closely on SARS-CoV-2, ”says Lucía Chemes.
It was not always easy to work under lock-in conditions. One of the co-authors of the study, Elizabeth Martínez Perez of the Leloir Institute in Argentina, for example, could not return from her secondment in the Gibson team at EMBL Heidelberg.
At the same time, Manjeet Kumar had to adjust to the homework when his children were in the area. ‘I got kind support from our housewife to work in the attic of the building, even though the internet signal did not reach there! Eventually I bought a 35 meter internet cable and connected it to the attic. After it was set up, I gained momentum in the project, ‘he recalls.
For many, working on SARS-CoV-2 research has been an inspiring experience. ‘We wanted to contribute to the fight against COVID-19. It set us a common goal, ‘says Toby Gibson. Bálint Mészáros agrees. “It’s weird, exciting and a little disturbing groundbreaking work in the COVID-19 field,” he says. “As researchers, we are enthusiastic about inventing pieces from biology, but at the same time we are very excited to be working on such an important topic.”
Reference: “Short Candidates for Linear Motifs in the Cell Input System Used by SARS-CoV-2 and Their Potential Therapeutic Implications” by Bálint Mészáros, Hugo Sámano-Sánchez, Jesús Alvarado-Valverde, Jelena Calyševa, Elizabeth Martínez-Pérez, Renato Alves , Denis C. Shields, Manjeet Kumar, Friedrich Rippmann, Lucía B. Chemes and Toby J. Gibson, January 12, 2021, Science signal.
DOI: 10.1126 / scisignal.abd0334