High affinity modified ACE2 receptors prevent SARS-CoV-2 infection

BioRxiv : the Preprint Server for Biology
Y. HiguchiAtsushi Hoshino

Abstract

The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor via receptor binding domain (RBD) to enter into the cell. Inhibiting this interaction is a main approach to block SARS-CoV-2 infection and it is required to have high affinity to RBD independently of viral mutation for effective protection. To this end, we engineered ACE2 to enhance the affinity with directed evolution in human cells. Three cycles of random mutation and cell sorting achieved more than 100-fold higher affinity to RBD than wild-type ACE2. The extracellular domain of modified ACE2 fused to the Fc region of the human immunoglobulin IgG1 had stable structure and neutralized SARS-CoV-2 pseudotyped lentivirus and authentic virus with more than 100-fold lower concentration than wild-type. Engineering ACE2 decoy receptors with directed evolution is a promising approach to develop a SARS-CoV-2 neutralizing drug that has affinity comparable to monoclonal antibodies yet displaying resistance to escape mutations of virus.

Citations

Jan 14, 2021·The Biochemical Journal·George M Burslem
Apr 27, 2021·Frontiers in Molecular Biosciences·Krishna K Narayanan, Erik Procko
Jul 8, 2021·ACS Central Science·Alexander NormanRichard J Payne

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