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Mol Ther
. 2023 Nov 15:S1525-0016(23)00620-2.
doi: 10.1016/j.ymthe.2023.11.019. Online ahead of print. A cardiotoxicity-eliminated ACE2 variant as a pan-inhibitor against coronavirus cell invasion
Han Feng 1 , Linpu Yang 1 , Hang Yang 2 , Dongwan Cheng 1 , Min Li 3 , Eli Song 4 , Tao Xu 5
Affiliations
Human recombinant ACE2 (hrACE2) has been highly anticipated as a successful COVID-19 treatment; however, its potential to cause cardiac side effects has given rise to many concerns. Here, we developed a cardiotoxicity-eliminated hrACE2 variant, which had four mutation sites within hrACE2 (H345L, H374L, H378L, H505L) and was named as hrACE2-4mu. hrACE2-4mu has a consistent binding affinity with the variant SARS-CoV-2 spike proteins (SPs) and an efficient ability to block SP-induced SARS-CoV-2 entry into cells. In golden hamsters, injection of purified wild-type (WT) hrACE2 rescues the early stages of pneumonia caused by the SPs of the WT, delta, and omicron variants with reduced inflammatory cell infiltration. However, long-term injection of WT hrACE2 induces undesired cardiac fibrosis, as demonstrated by upregulated fibronectin and collagen expression. Our newly developed hrACE2-4mu showed the similar protective abilities against a series of coronavirus cell invasions as WT hrACE2, meanwhile it did not cause apparent cardiac side effects. Thus, we generated a cardiotoxicity-eliminated variant of hrACE2 as a pan-inhibitor against coronavirus cell invasion, providing a potential novel strategy for the treatment of COVID-19 and other coronaviruses.
. 2023 Nov 15:S1525-0016(23)00620-2.
doi: 10.1016/j.ymthe.2023.11.019. Online ahead of print. A cardiotoxicity-eliminated ACE2 variant as a pan-inhibitor against coronavirus cell invasion
Han Feng 1 , Linpu Yang 1 , Hang Yang 2 , Dongwan Cheng 1 , Min Li 3 , Eli Song 4 , Tao Xu 5
Affiliations
- PMID: 37974399
- DOI: 10.1016/j.ymthe.2023.11.019
Human recombinant ACE2 (hrACE2) has been highly anticipated as a successful COVID-19 treatment; however, its potential to cause cardiac side effects has given rise to many concerns. Here, we developed a cardiotoxicity-eliminated hrACE2 variant, which had four mutation sites within hrACE2 (H345L, H374L, H378L, H505L) and was named as hrACE2-4mu. hrACE2-4mu has a consistent binding affinity with the variant SARS-CoV-2 spike proteins (SPs) and an efficient ability to block SP-induced SARS-CoV-2 entry into cells. In golden hamsters, injection of purified wild-type (WT) hrACE2 rescues the early stages of pneumonia caused by the SPs of the WT, delta, and omicron variants with reduced inflammatory cell infiltration. However, long-term injection of WT hrACE2 induces undesired cardiac fibrosis, as demonstrated by upregulated fibronectin and collagen expression. Our newly developed hrACE2-4mu showed the similar protective abilities against a series of coronavirus cell invasions as WT hrACE2, meanwhile it did not cause apparent cardiac side effects. Thus, we generated a cardiotoxicity-eliminated variant of hrACE2 as a pan-inhibitor against coronavirus cell invasion, providing a potential novel strategy for the treatment of COVID-19 and other coronaviruses.