Please use this identifier to cite or link to this item: http://conacyt.repositorioinstitucional.mx/jspui/handle/1000/7550
Integrin/TGF-Beta1 inhibitor GLPG-0187 blocks SARS-CoV-2 Delta and Omicron pseudovirus infection of airway epithelial cells which could attenuate disease severity
Kelsey Huntington
Lindsey Carlsen
Eui-Young So
Matthias Piesche
Olin Liang
Wafik El-Deiry
Acceso Abierto
Atribución-NoComercial-SinDerivadas
https://doi.org/10.1101/2022.01.02.22268641
https://www.medrxiv.org/content/10.1101/2022.01.02.22268641v1
As COVID-19 continues to pose major risk for vulnerable populations including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced inhibition of pseudovirus infection by GLPG-0187. Because integrins activate TGF-beta; signaling, we compared plasma levels of active and total TGF-beta; in COVID-19+ patients. Plasma TGF-beta1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-beta1 levels correlated with activated TGF-beta1 levels. In our preclinical studies, Omicron infects lower airway lung cells less efficiently than other COVID-19 variants. Moreover, inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and may mitigate COVID-19 severity through decreased TGF-beta1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.
medRxiv and bioRxiv
03-01-2022
Preimpreso
www.medrxiv.org
Inglés
Epidemia COVID-19
Público en general
VIRUS RESPIRATORIOS
Versión publicada
publishedVersion - Versión publicada
Appears in Collections:Artículos científicos

Upload archives