Therapies Targeting Capsid Proteins Show Promise for HIV-1

Therapies targeting capsid proteins show promise as candidates to combat drug resistance for human immunodeficiency virus type 1 (HIV-1) that antiretroviral therapies (ARTs) can cause, according to the results of a study published in Retrovirology.

Investigators said that capsid proteins, because of their antiviral design, have indispensable roles in HIV-1 cytoplasmic trafficking, immune evasion, reverse transcription, nuclear entry, integration, assembly, and maturation.

There are 49 FDA-approved medication for HIV. There are 7 categories: chemokine receptor antagonists attachment inhibitors; fusion inhibitors; integrase strand transfer inhibitors; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; post-attachment inhibitors; and protease inhibitors.

The ARTs have several limitations, including drug resistance, toxicity, viral transmission, virologic failure, and limited treatment options for those who are treatment-experienced, according to the study.

It is essential to develop novel HIV therapies to combat these limitations and research new therapeutic targets, investigators said.

By targeting the HIV-1 viral conical core, also known as the capsid or core, therapies could disrupt the process of assembly and/or disassembly of the virus, resulting in the suppression of the virus.

Investigators reviewed different compounds that target 5 sites of the capsid proteins: apical binding site, CAP-1 binding site, central pore binding site FG binding site, and 2-fold binding site.

They found that compounds that target the FG binding site, such as GS-6207 (lenacapavir; Gilead Sciences) and PF74 (Pfizer) have had success.

The development of PF74 was a major landmark, even though the drug was never in the clinic, according to the study results.

The drug “demonstrated sub-micromolar potency and serves as the backbone for some of the most promising current compounds, including PF74 analogues with increased potency, particularly against [capsid proteins] mutants that display resistance to PF74,” according to the study.

The core peptidic backbone of PF74 has also been applied to other capsid proteins targeting compounds, such as GS-6207, which is an extremely potent therapy that is in phase 2/3 clinical trials.

Although investigators concluded that it is the current most successful capsid inhibitor, there is little evidence as to whether the drug will cause resistance during use.

They called for further research into the FG binding site, as well as the impact of resistance-associated mutations, saying this will help promote the develop the development of antivirals that improve drug resistance.

Another notable finding of the study was that the CAP-1 binding site did not have a lot of clinical success because of low binding affinity.

However, the CAP-1 binding site demonstrated the potential of capsid proteins, as it was the first compound reported to target capsid proteins, investigators said.

This helped expand the field of HIV-1 capsid inhibitors for each of the 5 binding sites discussed.

Gilead Sciences and Merck have announced a promising treatment combination of GS-6207 and islatravir (EFdA; Merck), which is a long-acting therapeutic that targets the capsid proteins and reverses the transcriptase, investigators said.

Reference

McFadden WM, Snyder AA, Kirby KA et al. Rotten to the core: antivirals targeting the HIV-1 capsid core. Retrovirology. 2021;18(1):41. doi:10.1186/s12977-021-00583-z