In the

management of HIV/AIDS The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple ...

, HIV capsid inhibitors are antiretroviral medicines that target the

capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...

shell of the virus. Most current antiretroviral drugs used to treat HIV do not directly target the viral capsid. Because of this, drugs that specifically inhibit the HIV capsid are being developed in order to reduce the replication of HIV, and treat infections that have become resistant to current antiretroviral therapies.

History and background

HIV Capsid

The mechanism of HIV infection involves the transport and integration of the viral genome into the DNA of the host cell. This process involves both viral and cellular proteins which reverse transcribe the viral RNA to double-stranded DNA, and incorporate the viral DNA into the host cell genome. The capsid surrounding the viral RNA, nucleocapsids,

reverse transcriptase A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...

, and

integrase Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...

plays a key role in the infection process. The capsid is composed of amino- and carboxy-terminal domains that form hexameric and pentameric rings. These rings assemble to form a cone-shaped structure surrounding the viral RNA and proteins. Upon entering the cytoplasm of a host cell, the capsid goes through an unfolding process that releases the viral RNA and proteins into the cell. The uncoating process is a highly ordered multistep process in which the capsid is weakened and most or all capsid proteins are removed from the shell. Upsetting this process can have downstream effects that significantly reduce the infectivity of the virus. Because of this, capsid uncoating is a favorable target for antiretroviral medicines.

HIV Treatment

Current drugs administered in the treatment of HIV do not target the capsid. Instead, patients are given a cocktail of

reverse transcriptase inhibitors Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication ...

protease inhibitors Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...

integrase inhibitor Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, block ...

s, and

entry inhibitor Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D. HIV entr ...

s. These drugs have been successful on an epidemiologic and individual basis. With treatment, people infected by HIV are able to live long and healthy lives. As current treatments significantly reduce the mortality and morbidity of HIV, the disease is incurable but chronically manageable. Because patients typically need to take antiretroviral medications for the rest of their lives, long-term effects of

HIV treatment The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

are important to consider. Long term toxicological effects of antiretroviral treatments can sometimes cause secondary morbidities even when the viral count is low. Additionally, drug resistances can be acquired or transmitted due to suboptimal pharmokinetics or lack of patient adherence to treatment.

Therapeutic applications

Lenacapavir

Lenacapavir is a capsid inhibitor developed by

Gilead Sciences Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...

. It is in phase II/III of clinical trials. Preliminary reports show that Lenacapavir is more potent than current HIV treatments, and may function as a long-acting antiretroviral therapy that only needs to be administered every six months. Lenacapavir functions by binding to the hydrophobic pocket formed by two neighboring protein subunits in the capsid shell. This bond stabilizes the capsid structure and inhibits the functional disassembly of the capsid in infected cells. GS-CA1

Lenacapavir was approved for medical use in the European Union in August 2022, in Canada in November 2022, and in the United States in December 2022. Lenacapavir is the first capsid inhibitor to be FDA-approved for treating

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

GS-CA1

GS-CA1 is an experimental small-molecule capsid inhibitor developed by

. CS-CA1 and GS-6207 are analogues, with both molecules showing promising anti-HIV activity. GS-CA1 functions by binding directly to the HIV capsid. This bonding disrupts the uncoating process which inhibits both the release of viral RNA and proteins into the cytoplasm, and also inhibits the production of new capsid shells within the cell. Ebselen-2D-skeletal

Ebselen

Ebselen Ebselen (also called PZ 51, DR3305, and SPI-1005), is a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity. It acts as a mimic of glutathione peroxidase and can also react with peroxynitrite. It ...

was identified as a capsid inhibitor using a fluorescence assay on a library of pharmacological compounds. Ebselen covalently bonds to the C-terminal domain of the HIV capsid, which inhibits the uncoating process. Ebselen shows anti-HIV activity in infected cell lines.

Uracil-based drugs

Uracil based scaffolds such as bispyrimidine dione and tetrapyrimidine dione derivatives have shown activity as HIV-1 p24 capsid inhibitors in an ''in vitro'' setting but need further exploration.

References

{{Reflist Wikipedia Student Program HIV/AIDS Antiretroviral drugs Virology