What Is a Fusion Peptide and How Does It Work?
Understand how fusion peptides work, the small protein structures essential for membrane fusion in both viral infection and modern antiviral drug design.
The natural world depends on the constant separation and merging of biological membranes. These lipid barriers define the boundaries of cells and their internal compartments, but must sometimes be breached for transport, communication, or reproduction. This process of membrane fusion allows a virus to infect a cell, a sperm to fertilize an egg, and a neuron to release neurotransmitters. At the heart of this physical remodeling are specialized molecular tools known as fusion peptides, which initiate the process that allows two distinct membranes to become one.
Understanding Fusion Peptides: Nature and Origin
A fusion peptide is a short chain of amino acids, typically 15 to 30 residues long, that is part of a larger protein. These peptides are defined by their hydrophobic (water-repelling) character, with amino acid sequences rich in residues like glycine and alanine. This composition allows them to interact with the fatty lipid interior of a cell membrane.
These peptides are hidden segments within larger fusion proteins, such as those on the surface of viruses like influenza, HIV, and coronaviruses. In its inactive state, the fusion peptide is tucked away inside the protein. A specific trigger, like binding to a cell receptor, causes the protein to change shape and expose the fusion peptide.
Fusion proteins are classified by their structure. Class I fusion proteins, found in viruses like HIV and influenza, have their fusion peptide at one end of a protein subunit. This peptide is revealed after a cleavage event, which ensures it is deployed only when needed to start an infection.
The Fusion Mechanism: How Peptides Merge Membranes
Membrane fusion begins when the parent fusion protein receives an external signal, such as a drop in pH or binding to a receptor on a host cell. This trigger initiates a conformational change in the protein, unsheathing the previously hidden fusion peptide.
Once exposed, the hydrophobic fusion peptide inserts itself into the target cell’s membrane like a grappling hook, anchoring the virus to the host cell. The fusion protein is now in a “pre-hairpin” intermediate state, bridging the viral and cellular membranes.
Following insertion, the larger fusion protein refolds on itself in a motion similar to a collapsing spring. This refolding pulls the two membranes into extremely close proximity. The mechanical force overcomes the natural repulsion between the lipid bilayers, squeezing out water molecules from the space between them.
This forced proximity destabilizes the membranes. The outer layers (leaflets) of the viral and cell membranes mix, creating a connection called a hemifusion stalk. This state resolves into a fusion pore, a channel that connects the interiors of the virus and the cell, which then widens to release the virus’s genetic material.
Viral Entry: Fusion Peptides in Action
The influenza virus is taken into the host cell through an endosome, a membrane-bound vesicle. As the endosome matures, its internal environment becomes more acidic. This drop in pH triggers influenza’s hemagglutinin (HA) protein to refold, extend its fusion peptide, and fuse the viral and endosomal membranes to release its genome.
Human Immunodeficiency Virus (HIV) uses a different trigger for its gp41 fusion protein. The process begins when its partner protein, gp120, binds to the CD4 receptor on a human T-cell. This binding exposes the gp41 fusion peptide, which embeds into the T-cell’s membrane to initiate fusion directly at the cell surface.
The SARS-CoV-2 virus binds to the ACE2 receptor on a host cell via its Spike (S) protein. For fusion to proceed, the S protein must be cleaved by a host cell protease like TMPRSS2. This cleavage activates the S2 subunit containing the fusion peptide, allowing it to insert into the host membrane and drive fusion.
Harnessing Fusion Peptides: Medical and Research Frontiers
The role of fusion peptides in viral entry makes them a target for medical intervention, as blocking their action can stop a virus from entering a host cell. This strategy led to the development of antiviral drugs known as fusion inhibitors. One example is Enfuvirtide (Fuzeon), a synthetic peptide used to treat HIV that mimics a segment of the gp41 protein.
Enfuvirtide binds to the gp41 protein and prevents the conformational changes needed for membrane fusion. This approach jams the fusion machinery before it can pull the viral and cellular membranes together. Researchers are developing next-generation fusion inhibitors that are more potent and can combat drug-resistant viral strains.
Beyond direct inhibition, fusion peptides are also a focus in vaccine development. The fusion machinery is a target for neutralizing antibodies, which are immune proteins that can prevent infection. Many vaccine strategies are designed to elicit antibodies that bind to the fusion protein or peptide itself.
These antibodies can physically block the peptide from inserting into the host membrane or prevent the protein from refolding. By presenting the immune system with stabilized versions of these fusion components, researchers hope to train the body to recognize and neutralize the virus before it can cause disease.