HIV-1 Capsid Inhibitors as Antiretroviral Agents

Thenin-Houssier, Suzie; Valente, Susana T.

doi:10.2174/1570162x14999160224103555

Cited by 77 publications

(57 citation statements)

References 100 publications

(149 reference statements)

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“…The immature capsid then undergoes envelopment, budding, release, and maturation (Fig 1A). Interest in targeting HIV-1 assembly has been high, leading to numerous drug screens in recent years (9, 10). Of the compounds identified in these screens, the most successful have been those that bind to the capsid protein (CA).…”

Section: Introductionmentioning

confidence: 99%

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Reed

Solas²,

Kitaygorodskyy³

et al. 2020

Preprint

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Given the projected increase in multidrug resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life-cycle stages that are not targeted by antiretrovirals currently in use. Host-targeting drugs are of particular interest because they can offer a high barrier to resistance. Here we report identification of two related small molecules that inhibit HIV-1 late events, a stage of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and PBMCs and are effective against a primary isolate. They reduce virus production, likely by inhibiting a post-translational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag in situ; however, unexpectedly, selection experiments failed to identify compound-specific resistance mutations in gag or pol, even though known resistance mutations developed in a parallel nelfinavir selection. Thus, we hypothesized that instead of binding to Gag directly, these compounds might localize to assembly intermediates, the intracellular multiprotein complexes containing Gag and host factors that are formed during immature HIV-1 capsid assembly. Indeed, imaging of infected cells showed colocalization of the compound with two host enzymes found in assembly intermediates, ABCE1 and DDX6. While the exact target and mechanism of action of this chemotype remain to be determined, these findings suggest that these compounds represent first-in-class, host-targeting inhibitors of intracellular events in HIV-1 assembly.IMPORTANCEThe success of antiretroviral treatment for HIV-1 is at risk of being undermined by the growing problem of drug resistance. Thus, there is a need to identify antiretrovirals that act on viral life cycle stages not targeted by drugs in use, such as the events of HIV-1 Gag assembly. To address this gap, we developed a compound screen that recapitulates the intracellular events of HIV-1 assembly, including viral-host interactions that promote assembly. This effort led to identification of a new chemotype that inhibits HIV-1 replication at nanomolar concentrations by inhibiting virus production. This compound colocalized with Gag and two host enzymes that facilitate capsid assembly but resistance selection did not result in compound-specific mutations in gag, suggesting that the chemotype does not directly target Gag. We hypothesize that this chemotype may represent a first-in-class inhibitor of virus production that acts by targeting a viral-host complex important for HIV-1 Gag assembly.

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Section: Introductionmentioning

confidence: 99%

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Reed

Solas²,

Kitaygorodskyy³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Although the precise mechanisms of action for these compounds are currently unclear, several studies have suggested that small-molecule binding at this site may overly stabilize the capsid and perturb normal capsid disassembly processes, interfere with CA domain assembly processes that form intact capsids, or compete with nuclear import factor binding to the capsid, which is required for integration of the viral genome into the host cell 30,31 .…”

Section: Ligand Density Maps Reveal Alternate Binding Pocketsmentioning

confidence: 99%

Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP₆)

Yu¹,

Lee

Jin³

et al. 2020

Preprint

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Inositol hexakisphosphates (IP 6 ) are cellular cofactors that promote the assembly of mature capsids of the human immunodeficiency virus (HIV). These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP 6 increases the stable life times of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP 6 . We find that capsid hexamers and pentamers have differential binding modes for IP 6 . Ligand density calculations show three sites of interaction with IP 6 including at a known capsid-inhibitor binding pocket. Free energy calculations demonstrate that IP 6 preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly.These results elucidate the molecular role of IP 6 in stabilizing and assembling the retroviral capsid.Pittsburgh Supercomputing Center 17 . Similar to prior studies, IP 6 was initially added to the bulk solvent, approximately 10 Å away from any non-water molecules 18,19 . Four systems each for the CA hexamer and pentamer were prepared with IP 6 in randomized positions in bulk solvent, and selected for longer timescale simulations on Anton 2 (see: Materials and Methods for a complete description). In aggregate, the AA MD simulations totaled 32 µs for the hexamer and pentamer systems. In all cases, IP 6 was found to bind to the pore of the capsomere.

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“…A recent review discussed the inhibition of HIV-1 capsid assembly by small molecule compounds and their therapeutic potential [91]. This is an elegant option even for proteins that were supposed to be undruggable.…”

Section: Inhibitorsmentioning

confidence: 99%

Assemblins as maturational proteases in herpesviruses

Zühlsdorf

Hinrichs

2017

Journal of General Virology

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During assembly of herpesvirus capsids, a protein scaffold self-assembles to ring-like structures forming the scaffold of the spherical procapsids. Proteolytic activity of the herpesvirus maturational protease causes structural changes that result in angularization of the capsids. In those mature icosahedral capsids, the packaging of viral DNA into the capsids can take place. The strictly regulated protease is called assemblin. It is inactive in its monomeric state and activated by dimerization. The structures of the dimeric forms of several assemblins from all herpesvirus subfamilies have been elucidated in the last two decades. They revealed a unique serine-protease fold with a catalytic triad consisting of a serine and two histidines. Inhibitors that disturb dimerization by binding to the dimerization area were found recently. Additionally, the structure of the monomeric form of assemblin from pseudorabies virus and some monomer-like structures of Kaposi's sarcoma-associated herpesvirus assemblin were solved. These findings are the proof-of-principle for the development of new anti-herpesvirus drugs. Therefore, the most important information on this fascinating and unique class of proteases is summarized here.

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HIV-1 Capsid Inhibitors as Antiretroviral Agents

Cited by 77 publications

References 100 publications

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP₆)

Assemblins as maturational proteases in herpesviruses

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HIV-1 Capsid Inhibitors as Antiretroviral Agents

Cited by 77 publications

References 100 publications

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Identification of an antiretroviral small molecule that appears to be a host-targeting inhibitor of HIV-1 assembly

Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP6)

Assemblins as maturational proteases in herpesviruses

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Atomic-scale Characterization of Mature HIV-1 Capsid Stabilization by Inositol Hexakisphosphate (IP₆)