Understanding the Viral Target: What is the mechanism of action of amantadine in influenza?

October 10, 2025 •

4 min read

Though once a frontline treatment, amantadine has not been recommended for influenza A treatment in the United States for many years due to widespread resistance. Its specific viral target reveals why its effectiveness was limited, answering the question: What is the mechanism of action of amantadine in influenza?.

Quick Summary

Amantadine inhibits influenza A by blocking the M2 proton channel, a protein crucial for viral uncoating and replication, thereby preventing the release of genetic material into the host cell.

Key Points

M2 Protein Target: Amantadine works by specifically blocking the M2 proton channel, a transmembrane protein found in the influenza A virus.
Inhibition of Uncoating: By blocking the M2 protein, amantadine prevents the acidification of the viral core, which is a critical step for the virus to uncoat and release its genetic material inside the host cell.
Influenza A Specificity: The drug is only effective against influenza A viruses because influenza B viruses possess a different protein that is not inhibited by amantadine.
Widespread Resistance: Due to the rapid mutation rate of influenza A, widespread resistance to amantadine emerged, primarily caused by mutations like S31N in the M2 protein.
No Longer Recommended for Flu: Because of high levels of resistance, major health organizations like the CDC no longer recommend amantadine for treating or preventing influenza.
Alternative Therapeutic Use: Amantadine is now predominantly used to treat Parkinson's disease, where its mechanism involves modulating dopamine and acting as an NMDA receptor antagonist, a separate action from its antiviral properties.

The Crucial Role of the Influenza M2 Protein

To understand amantadine's mechanism, one must first recognize the function of the M2 protein in the influenza A virus. After the influenza virus attaches to a host cell, it is taken inside in a compartment called an endosome. To replicate, the virus must 'uncoat,' a process that involves releasing its genetic material from its protective shell into the host cell's cytoplasm. This uncoating process is triggered by a low pH environment within the endosome.

The M2 protein, a tetrameric proton channel, sits in the viral membrane and is activated by the acidic pH in the endosome. This activation allows hydrogen ions to flow from the endosome into the virus particle. The resulting acidification of the viral core facilitates the uncoating process, which is essential for replication. Without a functional M2 protein to acidify the viral interior, the virus cannot uncoat, and the replication cycle is halted.

Amantadine's Blockade: The Mechanism in Detail

Amantadine and its chemical relative, rimantadine, are classified as adamantanes, a class of antiviral drugs that target the M2 ion channel. The core of amantadine's mechanism of action involves physically blocking the M2 protein's channel. The amantadine molecule enters the channel pore and effectively plugs it, preventing the passage of hydrogen ions. This action specifically affects influenza A viruses, as influenza B viruses have a structurally different protein called NB that is not affected by amantadine.

By inhibiting the M2 proton channel, amantadine prevents the crucial acidification of the viral core. The viral ribonucleoproteins, which contain the viral genetic material, therefore remain trapped within the virus and cannot be released into the cytoplasm. This effectively stops the replication process at an early stage.

The Rise of Resistance and Decline of a Drug

Amantadine's elegant mechanism was highly effective when the drug was first introduced. However, as with many antivirals, resistance quickly emerged due to the rapid mutation rate of the influenza virus. The resistance is primarily caused by specific mutations in the M2 protein, which alter the channel's structure so amantadine can no longer bind and block it. The most common mutation is a single amino acid substitution where serine is replaced by asparagine at position 31 (S31N). This mutation, along with others, became widespread over time.

Global Spread: Resistance emerged and spread globally, and by the mid-2000s, it was found at high rates in many circulating influenza A strains, particularly H3N2.
CDC Recommendation Change: As a result of this widespread resistance, the Centers for Disease Control and Prevention (CDC) formally recommended against using amantadine and rimantadine for influenza treatment or prophylaxis.

Comparison of Influenza Antivirals


Feature	Amantadine	Oseltamivir (Tamiflu)	Baloxavir (Xofluza)
Mechanism of Action	M2 ion channel inhibitor, blocking viral uncoating.	Neuraminidase inhibitor, preventing new virus particles from leaving infected cells.	Cap-dependent endonuclease inhibitor, blocking viral gene transcription.
Target	M2 protein of influenza A only.	Neuraminidase of both influenza A and B.	Polymerase of both influenza A and B.
Active Viruses	Influenza A.	Influenza A and B.	Influenza A and B.
Resistance	Widespread due to M2 mutations, rendering it obsolete for influenza.	Resistance can occur but is less common and monitored by health authorities.	Resistance can develop, with some studies showing reduced susceptibility.
Current Usage for Flu	Not recommended by major health authorities like the CDC.	Recommended for treatment and prophylaxis.	Recommended for treatment.

Amantadine Today: A Shift in Therapeutic Use

Although amantadine's antiviral career for influenza has effectively ended, the drug found a second life due to its neuropharmacological effects, which are distinct from its antiviral mechanism. Amantadine is now widely used to treat Parkinson's disease and related conditions. In this context, it acts on dopamine neurons, increasing dopamine release and blocking dopamine reuptake. It also functions as a weak non-competitive antagonist of the NMDA receptor. These effects help to alleviate the motor symptoms associated with Parkinson's, such as dyskinesia and rigidity.

Conclusion

Amantadine's history as an antiviral is a classic case study in the fight against rapidly evolving viruses. Its mechanism of action, the inhibition of the influenza A M2 protein, was initially effective but was ultimately overcome by the virus's ability to mutate. The subsequent rise of resistance highlights the ongoing challenge of developing durable antiviral therapies. For modern influenza management, the focus has shifted to newer drug classes, such as neuraminidase inhibitors, which have different mechanisms of action. Today, amantadine's legacy lies in its alternative application as a valuable treatment for neurological disorders like Parkinson's disease, demonstrating how a drug's pharmacological profile can lead to unexpected therapeutic uses.

For more information on current influenza antiviral recommendations, you can visit the CDC's official guidelines.

Frequently Asked Questions

Amantadine stops the influenza A virus from replicating by blocking its M2 protein, a proton channel. This blockage prevents the viral core from becoming acidic, a necessary step for the virus to release its genetic material and begin replicating inside the host cell.

Amantadine is no longer used for influenza treatment because the virus developed widespread resistance to the drug through mutations in the M2 protein. These mutations, like the S31N substitution, changed the M2 channel's structure, preventing amantadine from binding effectively.

No, amantadine is only effective against influenza A viruses. It has no effect on influenza B because influenza B viruses do not have an M2 protein, instead using a different protein that amantadine cannot inhibit.

Today, amantadine's primary therapeutic use is for treating Parkinson's disease. It helps manage motor symptoms like dyskinesia and rigidity by affecting dopamine and glutamate pathways in the brain.

The mechanisms are distinct. For its antiviral action, amantadine blocks the M2 protein of the influenza A virus. For its antiparkinsonian action, it increases dopamine release and blocks NMDA receptors in the central nervous system.

Yes, current antiviral drugs for influenza include neuraminidase inhibitors (like oseltamivir) and cap-dependent endonuclease inhibitors (like baloxavir), which have different mechanisms of action and are effective against both influenza A and B.

Viral resistance to amantadine develops through genetic mutations in the M2 protein. These mutations prevent amantadine from binding to and blocking the ion channel, allowing the virus to continue its replication cycle.