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An ACE2 Microbody Containing a Single Immunoglobulin Fc Domain Is a Potent Inhibitor of SARS-CoV-2

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.celrep.2020.108528DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705358PubMed CentralArticle
http://dx.doi.org/10.17632/hsbn73xpkt.1DOIData
ORCID:
AuthorORCID
Tada, Takuya0000-0003-0779-9954
Chen, Jennifer S.0000-0002-7808-2670
Kaur, Ramanjit0000-0002-4627-415X
Stapleford, Kenneth A.0000-0002-7796-2254
Gristick, Harry0000-0002-1957-2821
Wilen, Craig B.0000-0003-2495-9403
Nimigean, Crina M.0000-0002-6254-4447
Landau, Nathaniel R.0000-0002-9997-1004
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
Funders:
Funding AgencyGrant Number
NIHDA046100
NIHAI122390
NIHAI120898
NIHRO1 GM124451
NIHP01-AI38398-S1
NIHK08 AI128043
Burroughs Wellcome FundUNSPECIFIED
Ludwig Family FoundationUNSPECIFIED
Mathers Charitable FoundationUNSPECIFIED
Vilcek/Goldfarb Fellowship Endowment FundUNSPECIFIED
NIHT32GM007205
NIHF30HL149151
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. (http://www.sciencedirect.com/science/article/pii/S2211124720315175)
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:02 Feb 2021 21:04

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