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A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids.
Wysocki, Jan; Ye, Minghao; Hassler, Luise; Gupta, Ashwani Kumar; Wang, Yuguo; Nicoleascu, Vlad; Randall, Glenn; Wertheim, Jason A; Batlle, Daniel.
  • Wysocki J; Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Ye M; Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Hassler L; Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Gupta AK; Comprehensive Transplant Center, Department of Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Wang Y; Comprehensive Transplant Center, Department of Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Nicoleascu V; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, Illinois.
  • Randall G; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, Illinois.
  • Wertheim JA; Comprehensive Transplant Center, Department of Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Batlle D; Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois d-batlle@northwestern.edu.
J Am Soc Nephrol ; 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-1197446
Semantic information from SemMedBD (by NLM)
1. Organoids PART_OF Kidney
Subject
Organoids
Predicate
PART_OF
Object
Kidney
2. ACE2 gene|ACE2 PART_OF soluble
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
soluble
3. Organoids LOCATION_OF COVID-19
Subject
Organoids
Predicate
LOCATION_OF
Object
COVID-19
4. angiotensin converting enzyme 2|ACE2 PART_OF soluble
Subject
angiotensin converting enzyme 2|ACE2
Predicate
PART_OF
Object
soluble
5. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
6. angiotensin converting enzyme 2|ACE2 INTERACTS_WITH ACE2 gene|ACE2
Subject
angiotensin converting enzyme 2|ACE2
Predicate
INTERACTS_WITH
Object
ACE2 gene|ACE2
7. Enzymatic Activity PROCESS_OF Patients
Subject
Enzymatic Activity
Predicate
PROCESS_OF
Object
Patients
8. NR4A2 protei PART_OF C1422064|59272
Subject
NR4A2 protei
Predicate
PART_OF
Object
C1422064|59272
9. Plasma LOCATION_OF ACE2 gene|ACE2
Subject
Plasma
Predicate
LOCATION_OF
Object
ACE2 gene|ACE2
10. Organoids PRODUCES TMPRSS2 gene|TMPRSS2
Subject
Organoids
Predicate
PRODUCES
Object
TMPRSS2 gene|TMPRSS2
11. Organoids PRODUCES ACE2 gene|ACE2
Subject
Organoids
Predicate
PRODUCES
Object
ACE2 gene|ACE2
12. Organoids PART_OF Kidney
Subject
Organoids
Predicate
PART_OF
Object
Kidney
13. ACE2 gene|ACE2 PART_OF soluble
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
soluble
14. Organoids LOCATION_OF COVID-19
Subject
Organoids
Predicate
LOCATION_OF
Object
COVID-19
15. angiotensin converting enzyme 2|ACE2 PART_OF soluble
Subject
angiotensin converting enzyme 2|ACE2
Predicate
PART_OF
Object
soluble
16. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
17. angiotensin converting enzyme 2|ACE2 INTERACTS_WITH ACE2 gene|ACE2
Subject
angiotensin converting enzyme 2|ACE2
Predicate
INTERACTS_WITH
Object
ACE2 gene|ACE2
18. Enzymatic Activity PROCESS_OF Patients
Subject
Enzymatic Activity
Predicate
PROCESS_OF
Object
Patients
19. NR4A2 protein, human|NR4A2 PART_OF ACE2 gene|ACE2
Subject
NR4A2 protein, human|NR4A2
Predicate
PART_OF
Object
ACE2 gene|ACE2
20. Plasma LOCATION_OF ACE2 gene|ACE2
Subject
Plasma
Predicate
LOCATION_OF
Object
ACE2 gene|ACE2
21. Organoids PRODUCES TMPRSS2 gene|TMPRSS2
Subject
Organoids
Predicate
PRODUCES
Object
TMPRSS2 gene|TMPRSS2
22. Organoids PRODUCES ACE2 gene|ACE2
Subject
Organoids
Predicate
PRODUCES
Object
ACE2 gene|ACE2
ABSTRACT

BACKGROUND:

There is an urgent need for approaches to prevent and treat SARS-CoV-2 infection. Administration of soluble ACE2 protein acting as a decoy to bind to SARS-CoV-2 should limit viral uptake mediated by binding to membrane-bound full-length ACE2, and further therapeutic benefit should result from ensuring enzymatic ACE2 activity to affected organs in patients with COVID-19.

METHODS:

A short variant of human soluble ACE2 protein consisting of 618 amino acids (hACE2 1-618) was generated and fused with an albumin binding domain (ABD) using an artificial gene encoding ABDCon, with improved albumin binding affinity. Human kidney organoids were used for infectivity studies of SARS-CoV-2 in a BSL-3 facility to examine the neutralizing effect of these novel ACE2 variants.

RESULTS:

Whereas plasma ACE2 activity of the naked ACE2 1-618 and ACE2 1-740 lasted about 8 hours, the ACE2 1-618-ABD resulted in substantial activity at 96 hours, and it was still biologically active 3 days after injection. Human kidney organoids express ACE2 and TMPRSS2, and when infected with SARS-CoV-2, our modified long-acting ACE2 variant neutralized infection.

CONCLUSIONS:

This novel ACE2 1-618-ABD can neutralize SARS-CoV-2 infectivity in human kidney organoids, and its prolonged duration of action should ensure improved efficacy to prevent viral escape and dosing convenience.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Journal subject: Nephrology Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Journal subject: Nephrology Year: 2021 Document Type: Article