RESUMEN
Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.
Asunto(s)
Antivirales/farmacología , Artesunato/farmacología , Autofagia/efectos de los fármacos , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos , Mesilato de Imatinib/farmacología , Infliximab/farmacología , Pandemias , SARS-CoV-2/efectos de los fármacos , Antidepresivos/farmacología , Antivirales/uso terapéutico , Artesunato/uso terapéutico , Cloroquina/farmacología , Desarrollo de Medicamentos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/fisiología , Retículo Endoplásmico/virología , Endosomas/efectos de los fármacos , Endosomas/virología , Humanos , Hidroxicloroquina/farmacología , Mesilato de Imatinib/uso terapéutico , Infliximab/uso terapéutico , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/fisiología , Membranas Intracelulares/virología , Ivermectina/farmacología , Macrólidos/farmacología , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Niclosamida/farmacología , Niclosamida/uso terapéutico , ARN Viral/metabolismo , SARS-CoV-2/fisiología , Replicación ViralRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors might also play important roles in SARS-CoV-2 infection, providing new directions for antiviral treatments. GRP78 is a stress-inducible chaperone important for entry and infectivity for many viruses. Recent molecular docking analyses revealed putative interaction between GRP78 and the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (SARS-2-S). Here we report that GRP78 can form a complex with SARS-2-S and ACE2 on the surface and at the perinuclear region typical of the endoplasmic reticulum in VeroE6-ACE2 cells and that the substrate-binding domain of GRP78 is critical for this interaction. In vitro binding studies further confirmed that GRP78 can directly bind to the RBD of SARS-2-S and ACE2. To investigate the role of GRP78 in this complex, we knocked down GRP78 in VeroE6-ACE2 cells. Loss of GRP78 markedly reduced cell surface ACE2 expression and led to activation of markers of the unfolded protein response. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159) selected for its safe clinical profile in preclinical models depleted cell surface GRP78 and reduced cell surface ACE2 expression, as well as SARS-2-S-driven viral entry and SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78 in combination therapy.
Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , Proteínas de Choque Térmico/genética , Interacciones Huésped-Patógeno/genética , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/genética , Internalización del Virus/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Sitios de Unión , Chlorocebus aethiops , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/virología , Chaperón BiP del Retículo Endoplásmico , Regulación de la Expresión Génica , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/metabolismo , Humanos , Mutación , Unión Proteica , Dominios Proteicos , Multimerización de Proteína , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Transducción de Señal , Glicoproteína de la Espiga del Coronavirus/metabolismo , Respuesta de Proteína Desplegada , Células VeroRESUMEN
In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection.