In the management of HIV/AIDS, HIV capsid inhibitors are antiretroviral medicines that target the capsid shell of the virus. Most current antiretroviral drugs used to treat HIV do not directly target the viral capsid. [1] These have also been termed "Capsid-targeting Antivirals", "Capsid Effectors", and "Capsid Assembly Modulators (CAMs)". 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. [2]
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. [3]
The capsid surrounding the viral RNA, nucleocapsids, reverse transcriptase, and integrase 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. [4] 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.[ citation needed ]
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. [5]
Current drugs administered in the treatment of HIV do not target the capsid. Instead, patients are given a cocktail of reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry inhibitors. [6] 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. [7]
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 are important to consider. Long term toxicological effects of antiretroviral treatments can sometimes cause secondary morbidities even when the viral count is low. [7] Additionally, drug resistances can be acquired or transmitted due to suboptimal pharmokinetics or lack of patient adherence to treatment. [8]
Lenacapavir is a capsid inhibitor developed by Gilead Sciences. It functions by binding to the hydrophobic pocket formed by two neighboring protein subunits in the capsid shell. [9] This bond stabilizes the capsid structure and inhibits the functional disassembly of the capsid in infected cells. [9]
Lenacapavir was approved for medical use in the European Union in August 2022, [10] in Canada in November 2022, [11] [12] and in the United States in December 2022. [13] Lenacapavir is the first capsid inhibitor to be FDA-approved for treating HIV/AIDS. [13]
In 2003, the first compound to bind the HIV-1 capsid was reported and termed "CAP-1". [14] Since then, over 40 molecules have been reported to inhibit HIV-1 by binding capsid, with five distinct chemotypes described. [2] The binding pocket for Lenacapavir was first described in 2009, with the small molecule PF-3450074 (PF74) developed by Pfizer. [15] PF74 was not developed clinically due to its fast metabolic breakdown and poor bioavailability, but its binding pocket has been well characterized and frequently targeted. [2]
GS-CA1 is an experimental small-molecule capsid inhibitor developed by Gilead Sciences. CS-CA1 and GS-6207 are analogues, with both molecules showing promising anti-HIV activity. [9]
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. [16]
Ebselen 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-1 capsid, which inhibits the uncoating process. Ebselen shows anti-HIV activity in infected cell lines. [6]
Phage display was used to identify peptides that bind the HIV-1 capsid protein, and the most promising peptide inhibitor was the Capsid Assembly Inhibitor (CAI) peptide. [17] CAI prevented the formation of mature capsids, but its poor permeability in cells limited its use. [17] Other peptide inhibitors have been reported, [18] as well as next generation inhibitors with increased stability, permeability, and antiviral activity. [19] These peptides interact at the C-terminal domain of the HIV-1 capsid, similar to Ebselen. [2]
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. [20]
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus. Many retroviruses cause serious diseases in humans, other mammals, and birds.
Retroviral integrase (IN) is an enzyme produced by a retrovirus that integrates its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage integrases (recombinases) used in biotechnology, such as λ phage integrase, as discussed in site-specific recombination.
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.
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 drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.
Enfuvirtide (INN), sold under the brand name Fuzeon, is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of AIDS/HIV.
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, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.
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 of HIV and other retroviruses.
Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene. The alpha isoform of this protein, TRIM5α, is a retrovirus restriction factor, which mediates a species-specific early block to retrovirus infection.
Zinc finger inhibitors, or zinc ejectors, are substances or compounds that interact adversely with zinc fingers and cause them to release their zinc from its binding site, disrupting the conformation of the polypeptide chain and rendering the zinc fingers ineffective, thereby preventing them from performing their associated cellular functions. This is typically accomplished through chelation of the zinc binding site. As zinc fingers are known to be involved in m-RNA regulation, reverse transcription, protection of synthesized viral DNA, transcription inhibition, and initial integration processes, prevention of zinc finger function can have drastic effects on the function of the cell or virus.
Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome and packaging these copies, the virus continues infecting new hosts. Replication between viruses is greatly varied and depends on the type of genes involved in them. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm.
APOBEC3G is a human enzyme encoded by the APOBEC3G gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in innate anti-viral immunity. APOBEC3G belongs to the family of cytidine deaminases that catalyze the deamination of cytidine to uridine in the single stranded DNA substrate. The C-terminal domain of A3G renders catalytic activity, several NMR and crystal structures explain the substrate specificity and catalytic activity.
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.
The P24 capsid protein is the most abundant HIV protein with each virus containing approximately 1,500 to 3,000 p24 molecules. It is the major structural protein within the capsid, and it is involved in maintaining the structural integrity of the virus and facilitating various stages of the viral life cycle, including viral entry into host cells and the release of new virus particles. Detection of p24 protein's antigen can be used to identify the presence of HIV in a person's blood, however, more modern tests have taken their place. After approximately 50 days of infection, the p24 antigen is often cleared from the bloodstream entirely.
Peptide T is an HIV entry inhibitor discovered in 1986 by Candace Pert and Michael Ruff, a US neuroscientist and immunologist. Peptide T, and its modified analog Dala1-peptide T-amide (DAPTA), a drug in clinical trials, is a short peptide derived from the HIV envelope protein gp120 which blocks binding and infection of viral strains which use the CCR5 receptor to infect cells.
CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the process by which HIV, the virus that causes AIDS, enters cells. Hence antagonists of this receptor are entry inhibitors and have potential therapeutic applications in the treatment of HIV infections.
Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.
The first human immunodeficiency virus (HIV) case was reported in the United States in the early 1980s. Many drugs have been discovered to treat the disease but mutations in the virus and resistance to the drugs make development difficult. Integrase is a viral enzyme that integrates retroviral DNA into the host cell genome. Integrase inhibitors are a new class of drugs used in the treatment of HIV. The first integrase inhibitor, raltegravir, was approved in 2007 and other drugs were in clinical trials in 2011.
VIR-576 is an experimental drug that is under clinical trials for the treatment of HIV-1 infections. VIR-576 is synthetic peptide that binds to HIV-1's hydrophobic fusion peptide gp41, preventing the virus from inserting itself into a host cell's membrane to initiate an infection. This drug is a synthesized variant of a highly specific natural entry inhibitor designated as VIRIP.
RNA-targeting small molecules represent a class of small molecules, organic compounds with traditional drug properties that can bind to RNA secondary or tertiary structures and alter translation patterns, localization, and degradation.
HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.