Molecular mechanism of L-SP40 peptide and in vivo efficacy against EV-A71 in neonatal mice
Document Type
Article
Publication Date
12-15-2021
Abstract
Aims: Enterovirus A71 (EV-A71) is an etiological agent of hand foot and mouth disease (HFMD) and has the potential to cause severe neurological infections in children. L-SP40 peptide was previously known to inhibit EVA71 by prophylactic action. This study aimed to identify the mechanism of inhibition in Rhabdomyosarcoma (RD) cells and in vivo therapeutic potential of L-SP40 peptide in a murine model. Main methods: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Coimmunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouseadapted EV-A71. Key findings: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouseadapted virus with a drastic reduction in the viral loads in the blood (similar to 4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs). Significance: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71.
Keywords
Enterovirus A71 (EV-A71), Hand foot and mouth disease (HFMD), Antiviral, In vivo protection, Nucleolin, L-SP40 peptide
Divisions
pathology
Funders
Ministry of Higher Education, Malaysia under FRGS [FRGS/1/2018/SKK11/SYUC/03/3],[FRGS/1/2020/SKK06/SYUC/01/1],Centre for Virus and Vaccine Research, Sunway University
Publication Title
Life Sciences
Volume
287
Publisher
Pergamon-Elsevier Science Ltd
Publisher Location
THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND