Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo.

Autor: Kober DL; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Caballero Van Dyke MC; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Eitson JL; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Boys IN; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., McDougal MB; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Rosenbaum DM; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Schoggins JW; Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 05. Date of Electronic Publication: 2023 Oct 05.
DOI: 10.1101/2023.09.26.559550
Abstrakt: The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses the human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables rapid affinity purification of a dimeric protein by altering the active site to prevent autoproteolytic digestion of a C-terminal His 10 epitope tag. In cultured cells, mutant ACE2 competitively inhibits lentiviral vectors pseudotyped with spike from multiple SARS-CoV-2 variants, and infectious SARS-CoV-2. Moreover, the protein can be nebulized and retains virus-binding properties. We developed a system for delivery of aerosolized ACE2 to K18-hACE2 mice and demonstrate protection by our modified ACE2 when delivered as a prophylactic agent. These results show proof-of-concept for an aerosolized delivery method to evaluate anti-SARS-CoV-2 agents in vivo and suggest a new tool in the ongoing fight against SARS-CoV-2 and other ACE2-dependent viruses.
Competing Interests: Conflicts of Interest DLK and DMR have filed a provisional patent describing the ACE2T371W. J.W.S serves as a consultant to the United States Federal Trade Commission on matters related to COVID-19.
Databáze: MEDLINE
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