ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin α5ß1, and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin α5ß1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 h after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence, and improved lung histology in a majority of mice 72 h post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin α5 and αv (an α5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin α5ß1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 Drug Treatment , COVID-19/prevention & control , Oligopeptides/therapeutic use , SARS-CoV-2/physiology , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , COVID-19/virology , Genome, Viral , Humans , Integrins/metabolism , Liver/enzymology , Liver/pathology , Lung/pathology , Lung/virology , Male , Mice, Inbred C57BL , Mice, Transgenic , Oligopeptides/pharmacology , SARS-CoV-2/genetics , Staining and Labeling , Viral Load/geneticsABSTRACT
SARS-CoV-2 is a novel coronavirus that severely affects the respiratory system, is the cause of the COVID-19 pandemic, and is projected to result in the deaths of 2 million people worldwide. Recent reports suggest that SARS-CoV-2 also affects the central nervous system along with other organs. COVID-19-associated complications are observed in older people with underlying neurological conditions like stroke, Alzheimer's disease, and Parkinson's disease. Hence, we discuss SARS-CoV-2 viral replication and its inflammation-mediated infection. This review also focuses on COVID-19 associated neurological complications in individuals with those complications as well as other groups of people. Finally, we also briefly discuss the current therapies available to treat patients, as well as ongoing available treatments and vaccines for effective cures with a special focus on the therapeutic potential of a small 5 amino acid peptide (PHSCN), ATN-161, that inhibits SARS-CoV-2 spike protein binding to both integrin α5ß1 and α5ß1/hACE2.