Determinants of activity of the HIV-1 maturation inhibitor PA-457

Li, Feng; Zoumplis, Dorian; Matallana, C; Kilgore, Nicole; Reddick, Mary; Yunus, Abdul S.; Adamson, Catherine S.; Salzwedel, Karl; Martin, David E.; Allaway, Graham P.; Freed, Eric O.; Wild, Carl

doi:10.1016/j.virol.2006.07.023

Cited by 61 publications

(66 citation statements)

References 39 publications

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“…One class of maturation inhibitors is exemplified by 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (also called PA-457) [113,114], which inhibits HIV-1 replication in tissue culture and animal model systems, and is currently in Phase 2 clinical trials [115]. PA-457 inhibits Gag processing at the CA-SP1 junction and appears to bind directly to this site because the inhibitor is incorporated into assembling virions and because mutations at the CA-SP1 junction induce drug resistance [115][116][117][118]. PA-457 does not bind free Gag, however, and therefore presumably recognizes SP1 in its assembled conformation.…”

Section: Novel Maturation Inhibitors Block Gag Processing and Ca Assementioning

confidence: 99%

The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

409

422

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HIV assembly and replication proceed through formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is initiated by proteolytic processing of Gag, which induces conformational changes in the CA domain and results in assembly of the distinctive conical capsid. Retroviral capsids are organized following the principles of fullerene cones, and the hexagonal CA lattice is stabilized by three distinct interfaces. Recently identified inhibitors of viral maturation act by disrupting the final stage of Gag processing, or by inhibiting formation of a critical intermolecular CA-CA interface in the mature capsid. Following release into a new host cell, the capsid disassembles and host cell factors can potently restrict this stage of retroviral replication. Here, we review the structures of immature and mature HIV virions, focusing on recent studies that have defined the global organization of the immature Gag lattice, identified sites likely to undergo conformational changes during maturation, revealed the molecular structure of the mature capsid lattice, demonstrated that capsid architectures are conserved, identified the first capsid assembly inhibitors, and begun to uncover the remarkable biology of the mature capsid.

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Section: Novel Maturation Inhibitors Block Gag Processing and Ca Assementioning

confidence: 99%

The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

409

422

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“…Newly liberated CA protein rearranges around the nascent RTC, forming a closed polyhedral capsid. Since the orderly completion of the capsid shell is essential for the early stages of the replication cycle (1-3), the Gag lattice and the maturation process pose attractive targets for pharmacological intervention (4)(5)(6)(7)(8)(9)(10).…”

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confidence: 99%

Contributions of Charged Residues in Structurally Dynamic Capsid Surface Loops to Rous Sarcoma Virus Assembly

Heyrana

Goh

Perilla

et al. 2016

J Virol

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Extensive studies of orthoretroviral capsids have shown that many regions of the CA protein play unique roles at different points in the virus life cycle. The N-terminal domain (NTD) flexible-loop (FL) region is one such example: exposed on the outer capsid surface, it has been implicated in Gag-mediated particle assembly, capsid maturation, and early replication events. We have now defined the contributions of charged residues in the FL region of the Rous sarcoma virus (RSV) CA to particle assembly. Effects of mutations on assembly were assessed in vivo and in vitro and analyzed in light of new RSV Gag lattice models. Virus replication was strongly dependent on the preservation of charge at a few critical positions in Gag-Gag interfaces. In particular, a cluster of charges at the beginning of FL contributes to an extensive electrostatic network that is important for robust Gag assembly and subsequent capsid maturation. Second-site suppressor analysis suggests that one of these charged residues, D87, has distal influence on interhexamer interactions involving helix ␣7. Overall, the tolerance of FL to most mutations is consistent with current models of Gag lattice structures. However, the results support the interpretation that virus evolution has achieved a charge distribution across the capsid surface that (i) permits the packing of NTD domains in the outer layer of the Gag shell, (ii) directs the maturational rearrangements of the NTDs that yield a functional core structure, and (iii) supports capsid function during the early stages of virus infection. IMPORTANCEThe production of infectious retrovirus particles is a complex process, a choreography of protein and nucleic acid that occurs in two distinct stages: formation and release from the cell of an immature particle followed by an extracellular maturation phase during which the virion proteins and nucleic acids undergo major rearrangements that activate the infectious potential of the virion. This study examines the contributions of charged amino acids on the surface of the Rous sarcoma virus capsid protein in the assembly of appropriately formed immature particles and the maturational transitions that create a functional virion. The results provide important biological evidence in support of recent structural models of the RSV immature virions and further suggest that immature particle assembly and virion maturation are controlled by an extensive network of electrostatic interactions and long-range communication across the capsid surface. Infectious retrovirus particles are the end products of a complex multistage assembly process. In the early phase, the Gag polyprotein binds virion genomic RNA and is targeted to the plasma membrane, where it assembles a near-spherical immature protein lattice. As the virion leaves the cell by a budding process, the virally encoded protease PR is activated, initiating maturation. Cleavage of the Gag polyprotein into the structural proteins MA (matrix), CA (capsid), and NC (nucleocapsid) results in a large-scale re...

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“…Additionally, it has been demonstrated that BVM is incorporated into assembling virus particles in a Gag-dependent manner (55). Furthermore, nearly all reported BVM resistance mutations have mapped to the CA-SP1 junction or within SP1 (2,37,38,53,56), and the resistance mutants that have been tested incorporate less BVM into particles (53,55). Finally, BVM is able to prevent cleavage of CA from SP1 only in Gag assembled into particles, not in free Gag in solution (37,46).…”

mentioning

confidence: 99%

HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice

Keller

Adamson

Heymann

et al. 2011

J Virol

Self Cite

108

127

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Maturation of nascent virions, a key step in retroviral replication, involves cleavage of the Gag polyprotein by the viral protease into its matrix (MA), capsid (CA), and nucleocapsid (NC) components and their subsequent reorganization. Bevirimat (BVM) defines a new class of antiviral drugs termed maturation inhibitors. BVM acts by blocking the final cleavage event in Gag processing, the separation of CA from its C-terminal spacer peptide 1 (SP1). Prior evidence suggests that BVM binds to Gag assembled in immature virions, preventing the protease from accessing the CA-SP1 cleavage site. To investigate this hypothesis, we used cryo-electron tomography to examine the structures of (noninfectious) HIV-1 viral particles isolated from BVM-treated cells. We find that these particles contain an incomplete shell of density underlying the viral envelope, with a hexagonal honeycomb structure similar to the Gag lattice of immature HIV but lacking the innermost, NC-related, layer. We conclude that the shell represents a remnant of the immature Gag lattice that has been processed, except at the CA-SP1 sites, but has remained largely intact. We also compared BVMtreated particles with virions formed by the mutant CA5, in which cleavage between CA and SP1 is also blocked. Here, we find a thinner CA-related shell with no visible evidence of honeycomb organization, indicative of an altered conformation and further suggesting that binding of BVM stabilizes the immature lattice. In both cases, the observed failure to assemble mature capsids correlates with the loss of infectivity.

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Determinants of activity of the HIV-1 maturation inhibitor PA-457

Cited by 61 publications

References 39 publications

The structural biology of HIV assembly

The structural biology of HIV assembly

Contributions of Charged Residues in Structurally Dynamic Capsid Surface Loops to Rous Sarcoma Virus Assembly

HIV-1 Maturation Inhibitor Bevirimat Stabilizes the Immature Gag Lattice

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