In themanagement of HIV/AIDS,HIV capsid inhibitors areantiretroviral medicines that target thecapsid shell of the virus. This is in contrast to other antiretroviral drugs used to treat HIV, which 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]
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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, andintegrase 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]
In 2022, the capsid inhibitorlenacapavir received approval from theEuropean Medicines Agency,Health Canada, and the United StatesFood and Drug Administration as a first-in-class medication to treat HIV-1 infection.[6][7][8][9][10]
Lenacapavir functions by binding to the hydrophobic pocket formed by two neighboring protein subunits in the capsid shell.[11] This bond stabilizes the capsid structure and inhibits the functional disassembly of the capsid in infected cells.[11]
In the years prior to the development of capsid inhibitors, HIV patients were generally treated with a combination ofreverse transcriptase inhibitors,protease inhibitors,integrase inhibitors, andentry inhibitors.[12] Lenacapavir is approved for those who develop resistance to such regimens, for use in addition to other HIV treatments.[10]
In 2003, the first compound to bind the HIV-1 capsid was reported and termed "CAP-1".[13][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 byPfizer.[15] PF74 was not developed clinically due to its fast metabolic breakdown and poorbioavailability, but its binding pocket has been well characterized and frequently targeted.[2]
GS-CA1 is an experimental small-molecule capsid inhibitor developed byGilead Sciences. GS-CA1 and GS-6207 are analogues, with both molecules showing promising anti-HIV activity.[11]
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 afluorescence 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.[12]
Phage display was used to identifypeptides 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 anin vitro setting but need further exploration.[20]
This article incorporates text from this source, which is in thepublic domain.