---
_id: '10363'
abstract:
- lang: eng
text: Erythropoietin enhances oxygen delivery and reduces hypoxia-induced cell death,
but its pro-thrombotic activity is problematic for use of erythropoietin in treating
hypoxia. We constructed a fusion protein that stimulates red blood cell production
and neuroprotection without triggering platelet production, a marker for thrombosis.
The protein consists of an anti-glycophorin A nanobody and an erythropoietin mutant
(L108A). The mutation reduces activation of erythropoietin receptor homodimers
that induce erythropoiesis and thrombosis, but maintains the tissue-protective
signaling. The binding of the nanobody element to glycophorin A rescues homodimeric
erythropoietin receptor activation on red blood cell precursors. In a cell proliferation
assay, the fusion protein is active at 10−14 M, allowing an estimate of the number
of receptor–ligand complexes needed for signaling. This fusion protein stimulates
erythroid cell proliferation in vitro and in mice, and shows neuroprotective activity
in vitro. Our erythropoietin fusion protein presents a novel molecule for treating
hypoxia.
acknowledgement: This work was supported by funds from the Wyss Institute for Biologically
Inspired Engineering and the Boston Biomedical Innovation Center (Pilot Award 112475;
Drive Award U54HL119145). J.L., K.M.K., D.R.B., J.C.W. and P.A.S. were supported
by the Harvard Medical School Department of Systems Biology. J.C.W. was further
supported by the Harvard Medical School Laboratory of Systems Pharmacology. A.V.,
D.R.B. and P.A.S. were further supported by the Wyss Institute for Biologically
Inspired Engineering. N.G.G. was sponsored by the Army Research Office under Grant
Number W911NF-17-2-0092. The views and conclusions contained in this document are
those of the authors and should not be interpreted as representing the official
policies, either expressed or implied, of the Army Research Office or the U.S. Government.
The U.S. Government is authorized to reproduce and distribute reprints for Government
purposes notwithstanding any copyright notation herein. We sincerely thank Amanda
Graveline and the Wyss Institute at Harvard for their scientific support.
article_number: gzab025
article_processing_charge: No
article_type: original
author:
- first_name: Jungmin
full_name: Lee, Jungmin
last_name: Lee
- first_name: Andyna
full_name: Vernet, Andyna
last_name: Vernet
- first_name: Nathalie
full_name: Gruber, Nathalie
id: 2C9C8316-AA17-11E9-B5C2-8BC2E5697425
last_name: Gruber
- first_name: Kasia M.
full_name: Kready, Kasia M.
last_name: Kready
- first_name: Devin R.
full_name: Burrill, Devin R.
last_name: Burrill
- first_name: Jeffrey C.
full_name: Way, Jeffrey C.
last_name: Way
- first_name: Pamela A.
full_name: Silver, Pamela A.
last_name: Silver
citation:
ama: Lee J, Vernet A, Gruber N, et al. Rational engineering of an erythropoietin
fusion protein to treat hypoxia. Protein Engineering, Design and Selection.
2021;34. doi:10.1093/protein/gzab025
apa: Lee, J., Vernet, A., Gruber, N., Kready, K. M., Burrill, D. R., Way, J. C.,
& Silver, P. A. (2021). Rational engineering of an erythropoietin fusion protein
to treat hypoxia. Protein Engineering, Design and Selection. Oxford University
Press. https://doi.org/10.1093/protein/gzab025
chicago: Lee, Jungmin, Andyna Vernet, Nathalie Gruber, Kasia M. Kready, Devin R.
Burrill, Jeffrey C. Way, and Pamela A. Silver. “Rational Engineering of an Erythropoietin
Fusion Protein to Treat Hypoxia.” Protein Engineering, Design and Selection.
Oxford University Press, 2021. https://doi.org/10.1093/protein/gzab025.
ieee: J. Lee et al., “Rational engineering of an erythropoietin fusion protein
to treat hypoxia,” Protein Engineering, Design and Selection, vol. 34.
Oxford University Press, 2021.
ista: Lee J, Vernet A, Gruber N, Kready KM, Burrill DR, Way JC, Silver PA. 2021.
Rational engineering of an erythropoietin fusion protein to treat hypoxia. Protein
Engineering, Design and Selection. 34, gzab025.
mla: Lee, Jungmin, et al. “Rational Engineering of an Erythropoietin Fusion Protein
to Treat Hypoxia.” Protein Engineering, Design and Selection, vol. 34,
gzab025, Oxford University Press, 2021, doi:10.1093/protein/gzab025.
short: J. Lee, A. Vernet, N. Gruber, K.M. Kready, D.R. Burrill, J.C. Way, P.A. Silver,
Protein Engineering, Design and Selection 34 (2021).
date_created: 2021-11-28T23:01:28Z
date_published: 2021-11-01T00:00:00Z
date_updated: 2023-08-14T13:01:38Z
day: '01'
department:
- _id: CaGu
doi: 10.1093/protein/gzab025
external_id:
isi:
- '000746596900001'
pmid:
- '34725710'
intvolume: ' 34'
isi: 1
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1093/protein/gzab025
month: '11'
oa: 1
oa_version: Published Version
pmid: 1
publication: Protein Engineering, Design and Selection
publication_identifier:
eissn:
- 1741-0134
issn:
- 1741-0126
publication_status: published
publisher: Oxford University Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: Rational engineering of an erythropoietin fusion protein to treat hypoxia
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 34
year: '2021'
...