التفاصيل البيبلوغرافية
| العنوان: |
Abstract 11197: Nano-Triciribine Reduces SARS-CoV-2 Infection by Sequestering ACE2 and the Novel Host Factor LDLR |
| المؤلفون: |
Condor Capcha, Jose Manuel, Iansen Irion, Camila, Lambert, Guerline, CHAHDI, AHMED, Buchwald, Peter, Dykxhoorn, Derek, Farzaneh, Hamidreza, deo, Sapna, Daunert, Sylvia, Young, Karen C, Shehadeh, Lina A |
| المصدر: |
Circulation ; volume 144, issue Suppl_1 ; ISSN 0009-7322 1524-4539 |
| بيانات النشر: |
Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: |
2021 |
| الوصف: |
Introduction: People with previous CVD hospitalized for COVID-19 have elevated death rate. We reported that patients with diabetes and HF higher protein levels of the low density lipoprotein receptor (LDLR). We hypothesized that LDLR is a novel host factor for the SARS-CoV-2-Spike (S2S) protein that may be regulated by the Akt inhibitor Triciribine (TCN), a drug being tested in Phase III studies for breast cancer. We also hypothesized that nano-formulation of Triciribine (NanoTriciribine; NTCN) would enhance its efficacy and allow for intranasal delivery. Methods: Interactions between the recombinant proteins Spike-RBD (receptor binding domain), ACE2, LDLR and its ectodomains (EGFA-EFFB, C2-C5 and C2) were analyzed by binding assays and co-IP in HepG2, HK2, and 293T cells. Viral entry assays were performed with 2 S2S pseudoviruses using 293T cells + hACE2 and TMPRSS2 or Furin protease. The effect of NTCN or the LXR agonist GW-3965 on viral uptake (pseudotyped VSVΔG-GFP*S2S or chimera VSV-S2S-eGFP virus) was assessed. Akt, pAkt, ACE2, and LDLR levels were determined in 293T+hACE2 by flow cytometry. Assays were done in triplicates and 1-way-ANOVA with Tukey’s correction was used for statistics. Results: RBD protein binds modestly to the human LDLR (EC 50 :10μM) and its C2-C5 ectodomain (EC 50 :13.8μM). Co-IP revealed a novel and strong LDLR-ACE2 interaction in several human cell lines. LDLR overexpression in human cells increased the uptake of VSVΔG-GFP*S2S (FC=2.32;p<0.001) and chimera virus (FC=.33; p<.0001). NTCN and TCN each reduced pAkt/Akt ratio. 1μM TCN or NTCN reduced LDLR (7.2%;p<.01 & 15.6%;p<0.0001) and ACE2 (32%;p<0.05 & 44.7%;p<.01) cell surface expression, respectively. 1μM NTCN or GW-3965 reduced S2S viral entry by 64.2% (p<.0001) and 40.7% (p<.01), respectively, confirming a role for LDLR in S2S infection. In hACE2tg mice, chimera VSV-S2S caused significant lung infection as measured by qPCR, GFP expression in proximal and distal lung airway epithelial cells, and ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1161/circ.144.suppl_1.11197 |
| الإتاحة: |
https://doi.org/10.1161/circ.144.suppl_1.11197Test |
| رقم الانضمام: |
edsbas.B855BB2B |
| قاعدة البيانات: |
BASE |
