The First Capsid Inhibitor: Lenacapavir, a Shining Star in the Field of Anti-AIDS Drugs

Recently, Gilead Sciences announced that its novel HIV antiviral capsid inhibitor Lenacapavir (Sunlenca) received marketing authorization from the European Commission (EC) for the treatment of multidrug-resistant HIV in combination with other antiretroviral drugs Infected adult patients.

Lenacapavir, a "first-in-class" capsid inhibitor with a multi-stage mechanism of action, is the first HIV drug designed to achieve ultra-long-acting, biannual injections. Although its EC-approved indications are highly limited (in the case of multi-drug resistance) and require concomitant use with other oral drugs, rather than a single injection every 6 months, lenacapavir is still in the field of HIV treatment a huge breakthrough.


HIV and AIDS

HIV, the human immunodeficiency virus, was first discovered in 1983 and named as lymphadenopathy-associated virus (LAV), and later changed its name to human immunodeficiency virus or HIV (HIV). AIDS), commonly known as AIDS.

HIV is an RNA retrovirus composed of four parts: envelope, conical capsid core, reverse transcriptase and its RNA. It passes through two glycoproteins gp120 and gp41 on the membrane and its main human receptor CD4+T Cells undergo adsorption and fusion to penetrate the cell membrane, and use their RNA as a template to synthesize single-stranded DNA by reverse transcriptase, and then synthesize double-stranded DNA under the action of DNA polymerase. Through subsequent integration, transcription, and translation, a polypeptide chain is formed. The polypeptide chain undergoes proteolytic processing by viral protease, and its protein and RNA are assembled and budded on the cell membrane, thereby completing the replication process of the virus in vivo.

In fact, HIV infection itself will not cause the death of the patient, but it will attack the human immune system. In the case of HIV-related immunodeficiency, the infected person often develops cardiovascular disease and many malignant diseases, which affects the survival of the infected person. caused a great impact.


HIV Treatment History

It took four years since the virus was first discovered in 1983. Zidovdine was approved for marketing on March 19, 1987, becoming the first anti-AIDS drug. With its exact curative effect, zidovudine is also an important anti-AIDS drug today, and one of the most basic components of "cocktail therapy".

At present, the most effective treatment for HIV is "cocktail therapy", also known as high-efficiency antiretroviral therapy, which is to treat AIDS by using three or more antiviral drugs. Drug combination regimens to achieve maximum possible benefit, tolerability and compliance, and reduce the risk of resistance development.


Classic anti-AIDS drugs can be divided into six categories:

1. Nucleoside reverse transcriptase inhibitors (NRTIs): Similar in structure to viral deoxynucleotides, they competitively bind to viral reverse transcriptase, thereby inhibiting the action of reverse transcriptase and hindering viral synthesis. Its representative drugs include zidovudine, zalcitabine, stavudine, lamivudine, emtricitabine, etc.

2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Unlike nucleoside reverse transcriptase inhibitors, these drugs work by binding to the hydrophobic pocket near the HIV reverse transcriptase polymerization site. Its representative drugs include nevirapine, efavirenz and delavirdine.

3. Protease inhibitor (PI): By inhibiting the activity of protease, the protein precursor cannot be cleaved, so that mature virions cannot be formed. Its representative drugs include saquinavir, ritonavir, amprenavir, lopinavir, fosaprenavir, tipranavir, etc.

4. Fusion inhibitors (FIs): targeting N-HR or C-HR to inhibit the fusion activity of HIV, thereby preventing the virus from entering host cells. Its representative drug is Enfuvirtide.

5. Integrase inhibitors (INIs): These drugs inhibit the activity of integrase by competitively binding to the activation site of integrase, resulting in the inability of the virus to integrate into the host cell, thereby blocking the replication process of the virus. Its representative drug is raltegravir.

6. Co-receptor inhibitors (CRIs): The representative drug Maraviroc is a class of CCR5 antagonists, which prevents the virus from entering host cells by inhibiting the binding of CCR5 co-receptors to the glycoprotein gp120 on the viral membrane, blocking the Copy process.

Although the "cocktail" therapy has achieved remarkable results, other side effects and drug resistance problems other than AIDS have gradually emerged. More importantly, long-acting formulations are a whole new way to approach the goal of cure.


Shining Stars: Capsid Inhibitors

Lenacapavir, a first-in-class long-acting HIV inhibitor, is also a first-in-class capsid inhibitor with a multi-stage mechanism of action, primarily by stabilizing the conical shell of HIV genetic material and essential enzymes and thereby preventing infection Breakdown of the capsid in cells to inhibit HIV-1 replication.

Since its action and mechanism are different from those of classical anti-AIDS drugs, there is currently no known cross-resistance to other classes of anti-AIDS drugs. lenacapavir, formerly known as GS-6207 or GS-CA2, was developed from the optimization of PF-3450074 (PF74), a peptidomimetic compound built around a phenylalanine core with amino and carboxylic acid ends, respectively. The indole-3-acetic acid and aniline moieties were capped (Figure 3). PF74 interferes with the assembly and disassembly of the capsid, and binds to HIV-1 cofactors Nup153 and CPSF6, thereby inhibiting HIV replication.

The EC approval of lenacapavir is based on data from a double-blind, placebo-controlled, global, multicenter Phase II/III CAPELLA study, which aims to evaluate lenacapavir in combination with an optimized background therapy regimen for the treatment of multiple previously treated, multidrug-resistant HIV Efficacy and safety of patients.

RESULTS: In a population of patients with significant unmet medical need, 83% (n=30/36) of subjects receiving lenacapavir on top of the optimized background regimen achieved an undetectable viral load at week 52 ( <50 copies/mL). In addition, CD4 counts increased by an average of 83 cells/µL in CAPELLA subjects.

In terms of safety, no serious adverse events related to lenacapavir occurred during the trial.

The lenacapavir is approved for marketing in Europe and is suitable for all 27 EU member states, as well as Norway, Iceland and Liechtenstein. It is worth mentioning that in December last year, as many as 10 clinical trials of lenacapavir were stopped by the FDA due to compatibility issues between the drug solution and borosilicate glass vials. In May, the FDA lifted the clinical hold related to lenacapavir. In July 2022, the FDA accepted the resubmitted NDA application for lenacapavir with a Prescription Drug User Fee Act (PDUFA) action date designating December 27, 2022.