In a recent study posted to the medRxiv* pre-print server, a team of researchers demonstrated the inhibitory action of integrin/transforming growth factor beta 1 (TGF-β1) inhibitor GLPG0187 on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus infection of human small airway epithelial (HSAE) cells.
RGD (Arg-Gly-Asp) motif present in the receptor-binding domain (RBD) of the spike (S) of SARS-CoV-2 allows SARS-CoV-2 to infect HSAE cells via RGD-binding integrins (receptor sites), facilitating viral infection. While eight RGD-binding integrins are known (αvβ1, prednisone six a day αvβ3, αvβ5, αvβ6, αvβ8, α5β1, α8β1, and αIIbβ3) that can potentially impact SARS-CoV-2 pathogenesis, a recent study has shown that αVβ3 inhibits spread of SARS-CoV-2 to other organs from the lungs. Furthermore, integrins can activate TGF-β, a growth factor that induces the chronic immune responses associated with SARS-CoV-2 severity.
About the study
Since integrins activate TGF-β signaling, the researchers of the present study compared plasma levels of active and total TGF-β in COVID-19-positive patients. Plasma TGF-β1 levels correlated with age, race, and the number of medications but not with a patient's gender upon presentation with COVID-19.
The researchers pre-treated HSAE cells with 1 or 2 µM GLPG-0187 for two hours, followed by spin-infection with pseudovirus. Experiments were also conducted using Omicron pseudovirus on HSAE cells with or without the integrin inhibitor GLPG-0187. Similarly, HSAE cells were pre-treated with MEK inhibitor (MEKi) VS-6766 to evaluate its inhibitory effect on pseudovirus infections.
Pre-treatment of HSAE cells with the pan-integrin inhibitor GLPG0187 effectively blocked multiple SARS-CoV-2 variants in HSAE cells in a dose-dependent manner. However, its inhibitory action resulted in the most significant decrease in pseudovirus infection by the Delta variant. Consistent with the findings of a recent study by Meng et al., the current study showed that Omicron infected HSAE cells less significantly than the D614G and Delta variant pseudovirus.
The pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. In addition, combination treatment with mitogen-activated protein kinase inhibitor (MEKi) compound VS-6766 and GLPG-0187 enhanced the inhibition of pseudovirus infection compared to treatment with either VS6766 or GLPG-0187.
Total plasma TGF-β1 levels correlated with activated TGF-β1 levels. There was a significant correlation between TGF-β1 concentration (pg/mL) and age and ethnicity, with notably higher levels of TGF-β1 in White, Hispanic/Latino populations, and notably lower levels in Black, Asian/Pacific Islander populations. Also, TGF-β1 levels substantially decreased in patients who received two to four medications after reporting COVID-19 to the Emergency Department (ED), compared to those who received only one or no medication at all. Also, TGF-β1 levels in patients increased with increasing COVID severity, as shown by their COVID-19 severity score (CSS).
The current preclinical study showed that the integrin/TGF-β1 inhibitor GLPG-0187 inhibited the infection of multiple pseudovirus variants including the highly transmissible Delta variant (prevalent since August 2021) and the Omicron variant (which became the most prevalent variant in December 2021), in HSAE cells.
As HSAE cells have low angiotensin-converting enzyme 2 (ACE2) expression, alternative targets such as RGD-binding integrins may have particular value for COVID-19 treatment. The study findings also suggested that combination treatment with a MEKi enhanced the inhibitory effect of GLPG-0187. This study finding is clinically relevant as GLPG0187 is in a phase I trial for solid tumor treatment and has shown a favorable toxicity profile in patients. In addition to inhibiting viral infection, integrin inhibition could also benefit COVID-19 patients by reducing levels of active TGF-β, as integrins are regulators of TGF-β activation.
Furthermore, the study results support the findings of other studies reporting GLPG-0187 treatment may benefit populations of COVID-19 patients with high levels of TGF-β1. TGF-β1 levels are higher in elderly, White, and Hispanic/Latino patients, and patients who received few medications in the ED, have more symptoms, have a high CSS, and have a history of chronic kidney disease.
Overall, the study results suggest that integrin inhibitors have the potential to both prevent infection with SARS-CoV-2, including the Delta and Omicron variants, and to decrease TGF-β levels, resulting in a decrease in COVID-19 severity, hospitalization, and death, especially in vulnerable and unvaccinated populations. These therapeutic strategies should be further tested in clinical trials, particularly with unvaccinated, immunosuppressed, or other populations with pre-existing health conditions for validation of the study findings.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Kelsey E. Huntington, Lindsey Carlsen, Eui-Young So, Matthias Piesche, Olin Liang, Wafik El-Deiry. (2021). Integrin/TGF-Beta1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells which could attenuate disease severity. medRxiv. doi: https://doi.org/10.1101/2022.01.02.22268641 https://www.medrxiv.org/content/10.1101/2022.01.02.22268641v1
Posted in: Genomics | Medical Science News | Medical Research News
Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Chronic, Chronic Kidney Disease, Compound, Coronavirus, Coronavirus Disease COVID-19, covid-19, Enzyme, Growth Factor, Kidney, Kidney Disease, Kinase, Kinase Inhibitor, Lungs, MEK Inhibitor, Omicron, Preclinical, Protein, Pseudovirus, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Tumor
Neha Mathur has a Master’s degree in Biotechnology and extensive experience in digital marketing. She is passionate about reading and music. When she is not working, Neha likes to cook and travel.
Source: Read Full Article