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A Fluorogenic Peptide Cleavage Assay to Screen for Proteolytic Activity: Applications for coronavirus spike protein activation
Published on: January 9, 2019
Lipidation increases antiviral activities of coronavirus fusion-inhibiting peptides
Jung-Eun Park1, Tom Gallagher1
1Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60153, USA.
Abstract:
Coronaviruses (CoVs) can cause life-threatening respiratory diseases. Their infectious entry requires viral spike (S) proteins, which attach to cell receptors, undergo proteolytic cleavage, and then refold in a process that catalyzes virus-cell membrane fusion. Fusion-inhibiting peptides bind to S proteins, interfere with refolding, and prevent infection. Here we conjugated fusion-inhibiting peptides to various lipids, expecting this to secure peptides onto cell membranes and thereby increase antiviral potencies. Cholesterol or palmitate adducts increased antiviral potencies up to 1000-fold. Antiviral effects were evident after S proteolytic cleavage, implying that lipid conjugates affixed the peptides at sites of protease-triggered fusion activation. Unlike lipid-free peptides, the lipopeptides suppressed CoV S protein-directed virus entry taking place within endosomes. Cell imaging revealed intracellular peptide aggregates, consistent with their endocytosis into compartments where CoV entry takes place. These findings suggest that lipidations localize antiviral peptides to protease-rich sites of CoV fusion, thereby protecting cells from diverse CoVs.
Insights
Lipid-conjugated antiviral peptides show significantly enhanced potency against coronaviruses (CoVs). These lipopeptides target viral fusion proteins, offering broad protection against CoV infections.
Area of Science:
- Virology
- Biochemistry
- Drug Discovery
Background:
- Coronaviruses (CoVs) cause severe respiratory illnesses.
- Viral entry depends on spike (S) proteins, which mediate fusion with host cells.
- Fusion-inhibiting peptides can block CoV infection by interfering with S protein refolding.
Purpose of the Study:
- To enhance the antiviral potency of fusion-inhibiting peptides.
- To investigate the effect of lipid conjugation on peptide localization and efficacy.
- To explore novel strategies for combating coronavirus infections.
Main Methods:
- Conjugating fusion-inhibiting peptides to lipids (cholesterol, palmitate).
- Assessing antiviral activity against CoV S protein-mediated entry.
- Utilizing cell imaging to track peptide localization within cells.
Main Results:
- Lipid-conjugated peptides (lipopeptides) increased antiviral potency up to 1000-fold.
- Lipopeptides suppressed CoV entry within endosomes, unlike lipid-free peptides.
- Cell imaging confirmed intracellular localization of lipopeptides at sites of viral entry.
Conclusions:
- Lipidation effectively localizes antiviral peptides to sites of CoV fusion activation.
- Lipopeptides offer enhanced protection against diverse coronaviruses.
- This strategy represents a promising approach for developing broad-spectrum antiviral therapies.
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