A mimetic peptide of ACE2 protects against SARS-CoV-2 infection and decreases pulmonary inflammation related to COVID-19

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Oliveira, Ernna H. ; Monteleone-Cassiano, Ana C. ; Tavares, Lucas ; Santos, Jadson C. ; Lima, Thais M. ; Gomes, Giovanni F. ; Tanaka, Pedro P. ; Monteiro, Cintia J. ; Munuera, Matheus ; Batah, Sabrina S. ; Fabro, Alexandre T. ; Faca, Vitor M. ; Masson, Ana P. ; Donadi, Eduardo A. ; Dametto, Mariangela ; Bonacin, Rodrigo ; Martins Jr, Ronaldo B. ; Arruda Neto, Eurico ; daSilva, Luis Lamberti P. ; Cunha, Thiago M. ; Passos, Geraldo A.

• Document type: Journal article
• Source: Antiviral Research; v. 229, p. 13-pg., 2024-07-18.

Abstract

Since human angiotensin-converting enzyme 2 (ACE2) serves as a primary receptor for SARS-CoV-2, characterizing ACE2 regions that allow SARS-CoV-2 to enter human cells is essential for designing peptide-based antiviral blockers and elucidating the pathogenesis of the virus. We identified and synthesized a 25-mer mimetic peptide (encompassing positions 22-46 of the ACE2 alpha-helix alpha 1) implicated in the S1 receptorbinding domain (RBD)-ACE2 interface. The mimetic (wild-type, WT) ACE2 peptide significantly inhibited SARS-CoV-2 infection of human pulmonary Calu-3 cells in vitro. In silico protein modeling predicted that residues F28, K31, F32, F40, and Y41 of the ACE2 alpha-helix alpha 1 are critical for the original, Delta, and Omicron strains of SARS-CoV-2 to establish the Spike RBD-ACE2 interface. Substituting these residues with alanine (A) or aspartic acid (D) abrogated the antiviral protective effect of the peptides, indicating that these positions are critical for viral entry into pulmonary cells. WT ACE2 peptide, but not the A or D mutated peptides, exhibited significant interaction with the SARS-CoV-2 S1 RBD, as shown through molecular dynamics simulations. Through identifying the critical amino acid residues of the ACE2 alpha-helix alpha 1, which is necessary for the Spike RBD-ACE2 interface and mobilized during the in vitro viral infection of cells, we demonstrated that the WT ACE2 peptide protects susceptible K18-hACE2 mice against in vivo SARS-CoV-2 infection and is effective for the treatment of COVID-19. (AU)

• FAPESP's process: 21/02081-4 - Effect of aire gene mutations induced by CRISPR-Cas9 on the transcriptional and post-transcriptional activity of mTEC cells and in its function on the thymocyte migration
• Grantee: Cintia Junia Monteiro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/10780-4 - Effect of CRISPR-Cas9-induced mutations in the Aire gene (APS1 syndrome) on protein conformation, mTEC cell transcriptome and their interaction with thymocytes
• Grantee: Geraldo Aleixo da Silva Passos Júnior
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/01182-1 - The functional characterization of AP-1 in the endolysosomal system and its relationship with the assembly of HIV-1
• Grantee: Lucas Alves Tavares
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/02418-9 - Molecular mechanisms of Oropouche Virus assembly
• Grantee: Luis Lamberti Pinto da Silva
• Support Opportunities: Regular Research Grants