Despite the significant advances that have been made in drug discovery to treat COVID-19, the rapid identification of new antivirals that could be easily transferred to the clinic continues to be very important, especially considering the emergence of drug-resistant variants. In this sense, the group led by Dr. María José Buzón, head of the HIV Translational Research laboratory within the Infectious Diseases research group at Vall d'Hebron Research, together with Dr. Meritxell Genescà, principal investigator of the same group, has developed a novel and rapid method for the study of SARS-CoV-2 that helps to identify potential treatments and to analyze its ability to modify local inflammation. The results of the study have been published in PLOS Pathogens.

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells is critical for identifying host-pathogen interactions and potential therapies. In this sense, the research team has used cell suspensions directly from primary human lung tissues (HLT) to develop a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as to screen for inhibitors of virus entry into cells and anti-inflammatory compounds.

HLT cells preserve main cell subpopulations and are readily susceptible to SARS-CoV-2 infection without the need for cell isolation or additional cell differentiation.

As part of the study, antiviral tests were performed on HLT cells with 39 drug candidates that have revealed that the method proposed by the researchers is highly reproducible and suitable for different SARS-CoV-2 variants. "This also facilitates the rapid identification of new compounds that are not detected by the systems we usually use for screening new candidates, such as the VeroE6 cell line," highlights Dr. Buzón. To reach this conclusion, they compared the result of testing the 39 drugs with antiviral tests on VeroE6 cells (kidney-derived epithelial cell lines). Specifically, 26.66% of the drugs showed some antiviral effect in HLT, but no activity was detected in VeroE6, and 6.67% only showed antiviral effects in VeroE6 cells.

Furthermore, they demonstrated that HLT cells can be successfully used for drug screening, not only against the D614G variant (emerged in the early 2020s), but also against the delta variant.

By using this method, researchers were also able to study the behavior of potential drugs to modulate inflammation. "Thus, we show that interferons do not modulate ACE2 expression and that the stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity," adds Dr. Genescà.

The study had the collaboration of the Nephrology and Thoracic Surgery and Lung Transplantation Departments of Vall d'Hebron University Hospital within the framework of the Task Force COVID-19, a multidisciplinary team formed by Vall d'Hebron professionals who work together to address the challenges posed by COVID-19. Researchers from IrsiCaixa, IDIBAPS, the University of Vic, the National Center of Microbiology of the Carlos III Institute of Health, the CIBER of Infectious Diseases and the CIBER of Respiratory Diseases (CIBERES) have also participated in the work.