What is the Mechanism of Action of Yeztugo?

In June 2025, the U.S. Food and Drug Administration (FDA) approved Yeztugo (lenacapavir) as the first and only twice-yearly injectable for HIV pre-exposure prophylaxis (PrEP). The mechanism of action of Yeztugo involves targeting the viral capsid at multiple points in the HIV-1 life cycle.

Quick Summary

Yeztugo (lenacapavir) is a first-in-class HIV capsid inhibitor that disrupts the viral life cycle by binding to the HIV capsid protein. This prevents nuclear import, interferes with assembly, and leads to malformed capsids.

Key Points

• Capsid Inhibitor: Yeztugo's active ingredient, lenacapavir, is a first-in-class, long-acting HIV-1 capsid inhibitor.

• Multistage Action: The medication interferes with several key stages of the HIV-1 life cycle.

• Blocks Nuclear Import: It prevents HIV-1 proviral DNA from being transported into the host cell's nucleus.

• Inhibits Assembly: Yeztugo disrupts the assembly and release of new viral particles.

• Malformed Capsids: By disrupting capsid formation, it causes the virus to assemble non-infectious capsid structures.

• High Affinity Binding: The drug binds with high affinity to the interfaces of the capsid protein (p24) subunits.

• Long-Acting Depot: As a twice-yearly injection, it creates a drug depot under the skin, providing sustained therapeutic levels.

• Reduces Adherence Burden: The twice-yearly dosing schedule significantly reduces the burden of adherence.

Yeztugo (lenacapavir), developed by Gilead Sciences, is a long-acting antiretroviral approved in 2025 for HIV pre-exposure prophylaxis (PrEP). Its mechanism of action involves targeting the HIV-1 capsid, a protein shell vital for viral function and replication. By disrupting the capsid at multiple points in the viral life cycle, Yeztugo provides sustained protection against infection.

The HIV Capsid as a Critical Target

The HIV-1 capsid, made of p24 protein subunits, is essential for the virus. It protects viral RNA and enzymes like reverse transcriptase, facilitates viral DNA transport into the host cell nucleus, and is crucial for forming new viral particles. Unlike many antiretrovirals that target enzymes, Yeztugo's mechanism directly interferes with this structural component. This makes it a first-in-class medication with a high barrier to resistance.

The Multistage Mechanism of Action of Yeztugo

Yeztugo binds with high affinity to the interface of capsid protein subunits, disrupting its normal function at multiple stages of the HIV life cycle.

1. Blocking Nuclear Import: Yeztugo prevents the transport of viral DNA into the host cell nucleus by interfering with cellular protein binding to the capsid.
2. Disrupting Virus Assembly and Release: The drug interferes with proteins needed for capsid subunit arrangement and assembly.
3. Causing Malformed Capsids: Yeztugo disrupts the final maturation of the capsid core, leading to rapid, disorganized polymerization. This results in unstable, non-infectious capsids.

Comparison with Other HIV Prevention Medications

Yeztugo's multistage mechanism distinguishes it from other PrEP options. NRTIs block reverse transcriptase, while INSTIs target the integrase enzyme. The table below outlines key differences.

Feature	Yeztugo (lenacapavir)	Truvada (emtricitabine/tenofovir)	Apretude (cabotegravir)
Drug Class	Capsid Inhibitor	Nucleoside Reverse Transcriptase Inhibitor (NRTI)	Integrase Strand Transfer Inhibitor (INSTI)
Dosing Frequency	Twice-yearly injection (subcutaneous)	Daily oral pill	Every two months injection (intramuscular)
Key Target(s)	HIV Capsid (p24) protein	Reverse Transcriptase enzyme	Integrase enzyme
Adherence Challenge	Minimal due to twice-yearly dosing schedule	Frequent non-adherence due to daily dosing	Potential non-adherence if injection appointments are missed

Clinical Significance and Therapeutic Benefits

Yeztugo's pharmacology offers advantages for HIV prevention. The long-acting injection provides sustained release over six months. This improves adherence compared to daily oral PrEP and maintains consistent drug levels.

Clinical trials showed high efficacy and superior prevention compared to daily oral PrEP. Yeztugo may be effective even with resistance to other antiretroviral classes. HIV testing before starting and before each subsequent injection is crucial to prevent resistance development in individuals with undiagnosed HIV. Yeztugo alone is not a complete treatment for existing HIV, and resistance can emerge. Consistent monitoring and adherence are essential. More information on clinical trials is available at Gilead's official website.

Conclusion

Yeztugo (lenacapavir) is a significant advancement in HIV prevention. Its capsid inhibitor mechanism disrupts the HIV-1 life cycle at multiple stages, including nuclear transport, assembly, and core formation. This multi-pronged attack ensures high effectiveness and a strong barrier against resistance. With a convenient twice-yearly injection, Yeztugo offers a powerful tool to improve adherence, reduce transmission risk, and help end the HIV epidemic.

Frequently Asked Questions

What is a capsid inhibitor?

A capsid inhibitor is a class of antiretroviral drugs that work by targeting the viral capsid, the protein shell that protects the virus's genetic material.

What are the different ways Yeztugo disrupts the HIV life cycle?

Yeztugo disrupts multiple stages of the HIV life cycle by blocking nuclear import of the viral DNA, interfering with virus assembly and release, and causing malformed capsid structures.

How is Yeztugo different from other PrEP medications?

Unlike daily oral PrEP or bimonthly injections, Yeztugo is a capsid inhibitor administered twice a year, offering sustained protection.

Why is a long-acting injectable like Yeztugo beneficial?

The twice-yearly injectable formulation significantly improves medication adherence and provides consistent drug levels for prolonged protection.

What is the importance of targeting the HIV capsid?

Targeting the HIV capsid disrupts multiple critical, capsid-dependent steps of the viral life cycle, providing a comprehensive approach to inhibiting HIV replication.

Does Yeztugo prevent other sexually transmitted infections?

No, Yeztugo is specifically for HIV prevention and does not protect against other sexually transmitted infections (STIs). It should be used as part of a comprehensive prevention strategy that includes safer sex practices like condom use.

Why is an HIV test required before receiving Yeztugo?

It is critical to confirm a negative HIV-1 status before and during Yeztugo treatment. If an individual has undiagnosed HIV and takes only Yeztugo, there is a risk of developing drug-resistant HIV.

What happens if a dose of Yeztugo is missed?

Missing scheduled injections can increase the risk of getting HIV. If a scheduled injection is delayed, oral tablets can be taken for up to 6 months on an interim basis until injections can be resumed.

Are there any interactions with other medications?

Yes, Yeztugo can interact with certain medications, including strong or moderate CYP3A inducers like rifampin or St. John's Wort. It is important to inform your healthcare provider of all other medicines you take.

What are the common side effects of Yeztugo?

The most common side effects include injection site reactions, such as pain, swelling, and nodules, along with headache and nausea.