Tada, Takuya and Fan, Chen and Chen, Jennifer S. and Kaur, Ramanjit and Stapleford, Kenneth A. and Gristick, Harry and Dcosta, Belinda M. and Wilen, Craig B. and Nimigean, Crina M. and Landau, Nathaniel R. (2020) An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2. Cell Reports, 33 (12). Art. No. 108528. ISSN 2211-1247. PMCID PMC7705358. https://resolver.caltech.edu/CaltechAUTHORS:20201202-101233646
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Abstract
Soluble forms of angiotensin-converting enzyme 2 (ACE2) have recently been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We report on an improved soluble ACE2, termed a “microbody,” in which the ACE2 ectodomain is fused to Fc domain 3 of the immunoglobulin (Ig) heavy chain. The protein is smaller than previously described ACE2-Ig Fc fusion proteins and contains an H345A mutation in the ACE2 catalytic active site that inactivates the enzyme without reducing its affinity for the SARS-CoV-2 spike. The disulfide-bonded ACE2 microbody protein inhibits entry of SARS-CoV-2 spike protein pseudotyped virus and replication of live SARS-CoV-2 in vitro and in a mouse model. Its potency is 10-fold higher than soluble ACE2, and it can act after virus bound to the cell. The microbody inhibits the entry of β coronaviruses and virus with the variant D614G spike. The ACE2 microbody may be a valuable therapeutic for coronavirus disease 2019 (COVID-19) that is active against viral variants and future coronaviruses.
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| Alternate Title: | ACE2 microbody blocks SARS-CoV-2 infection, A soluble ACE2 microbody protein fused to a single immunoglobulin Fc domain is a potent inhibitor of SARS-CoV-2 | ||||||||||||||||||||||||||
| Additional Information: | © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 11 August 2020, Revised 26 October 2020, Accepted 24 November 2020, Available online 1 December 2020. Published: December 22, 2020. We thank Michael Letko and Vincent Munster (NIH) for β coronavirus spike protein expression vectors. The work was funded by grants from the NIH (DA046100, AI122390, and AI120898 to N.R.L.; RO1 GM124451 to C.M.N.) and Pamela J. Bjorkman in support of H.G. (P01-AI38398-S1). C.B.W. was supported by the NIH (grant K08 AI128043), Burroughs Wellcome Fund, Ludwig Family Foundation, and the Mathers Charitable Foundation. T.T. was supported by the Vilcek/Goldfarb Fellowship Endowment Fund. J.S.C. was supported by NIH grants T32GM007205 and F30HL149151. Author Contributions: Conceptualization and Methodology, T.T., N.R.L., C.M.N., and C.B.W.; Investigation, T.T., C.F., J.S.C., R.K., K.A.S., H.G., and B.M.D.; Writing – Original Draft, T.T.; Writing – Review & Editing, N.R.L.; Funding Acquisition, N.R.L., C.M.N., C.B.W.; Resources, N.R.L., C.M.N., and C.B.W.; and Supervision, N.R.L. Declaration of Interests: A provisional patent application has been filed with the US Patent and Trademark Office. | ||||||||||||||||||||||||||
| Group: | COVID-19 | ||||||||||||||||||||||||||
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| Subject Keywords: | SARS-CoV-2; soluble ACE2; microbody; spike protein; lentiviral pseudotype; D614G; Fc fusion; ACE2 transgenic; coronavirus; entry inhibitor | ||||||||||||||||||||||||||
| Issue or Number: | 12 | ||||||||||||||||||||||||||
| PubMed Central ID: | PMC7705358 | ||||||||||||||||||||||||||
| Record Number: | CaltechAUTHORS:20201202-101233646 | ||||||||||||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20201202-101233646 | ||||||||||||||||||||||||||
| Official Citation: | Takuya Tada, Chen Fan, Jennifer S. Chen, Ramanjit Kaur, Kenneth A. Stapleford, Harry Gristick, Belinda M. Dcosta, Craig B. Wilen, Crina M. Nimigean, Nathaniel R. Landau, An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2, Cell Reports, Volume 33, Issue 12, 2020, 108528, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2020.108528. | ||||||||||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||||||||||||||||||||||
| ID Code: | 106875 | ||||||||||||||||||||||||||
| Collection: | CaltechAUTHORS | ||||||||||||||||||||||||||
| Deposited By: | Tony Diaz | ||||||||||||||||||||||||||
| Deposited On: | 02 Dec 2020 19:41 | ||||||||||||||||||||||||||
| Last Modified: | 11 Feb 2022 22:58 |
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