Peptides derived from the SARS-CoV-2 receptor binding motif bind to ACE2 but do not block ACE2-mediated host cell entry or pro-inflammatory cytokine induction.
PLoS One
; 16(11): e0260283, 2021.
Artículo
en Inglés
| MEDLINE | ID: covidwho-1523456
ABSTRACT
SARS-CoV-2 viral attachment and entry into host cells is mediated by a direct interaction between viral spike glycoproteins and membrane bound angiotensin-converting enzyme 2 (ACE2). The receptor binding motif (RBM), located within the S1 subunit of the spike protein, incorporates the majority of known ACE2 contact residues responsible for high affinity binding and associated virulence. Observation of existing crystal structures of the SARS-CoV-2 receptor binding domain (SRBD)-ACE2 interface, combined with peptide array screening, allowed us to define a series of linear native RBM-derived peptides that were selected as potential antiviral decoy sequences with the aim of directly binding ACE2 and attenuating viral cell entry. RBM1 (16mer) S443KVGGNYNYLYRLFRK458, RBM2A (25mer) E484GFNCYFPLQSYGFQPTNGVGYQPY508, RBM2B (20mer) F456NCYFPLQSYGFQPTNGVGY505 and RBM2A-Sc (25mer) NYGLQGSPFGYQETPYPFCNFVQYG. Data from fluorescence polarisation experiments suggested direct binding between RBM peptides and ACE2, with binding affinities ranging from the high nM to low µM range (Kd = 0.207-1.206 µM). However, the RBM peptides demonstrated only modest effects in preventing SRBD internalisation and showed no antiviral activity in a spike protein trimer neutralisation assay. The RBM peptides also failed to suppress S1-protein mediated inflammation in an endogenously expressing ACE2 human cell line. We conclude that linear native RBM-derived peptides are unable to outcompete viral spike protein for binding to ACE2 and therefore represent a suboptimal approach to inhibiting SARS-CoV-2 viral cell entry. These findings reinforce the notion that larger biologics (such as soluble ACE2, 'miniproteins', nanobodies and antibodies) are likely better suited as SARS-CoV-2 cell-entry inhibitors than short-sequence linear peptides.
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Antivirales
/
Péptidos
/
Unión Proteica
/
Internalización del Virus
/
Glicoproteína de la Espiga del Coronavirus
/
Enzima Convertidora de Angiotensina 2
Tipo de estudio:
Estudio observacional
/
Estudio pronóstico
Límite:
Humanos
Idioma:
Inglés
Revista:
PLoS One
Asunto de la revista:
Ciencia
/
Medicina
Año:
2021
Tipo del documento:
Artículo
País de afiliación:
Journal.pone.0260283
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