Antiviral Inhibition of the HIV-1 Capsid Protein

Tang, Chun; Loeliger, Erin; Kinde, Isaac; Kyere, Samson; Mayo, Keith; Barklis, Eric; Sun, Yan; Huang, Mingjun; Summers, Michael F.

doi:10.1016/s0022-2836(03)00289-4

Cited by 202 publications

(222 citation statements)

References 38 publications

Supporting

Mentioning

211

Contrasting

Order By: Relevance

“…Amide 1 HN-15 N backbone crosspeaks for MA were observed using standard two-dimensional heteronuclear sequential quantum correlation (HSQC) with pulse program hsqceftf3gp as described previously (70) (27,43). The association of compounds and MA was monitored by observing the changes in the amide 1 HN-15 N cross-peaks in the HSQC spectra of 15 N-labeled MA upon titration from 50 mM compound stock in DMSO as described previously (71) …”

Section: Methodsmentioning

confidence: 99%

Analysis of Small Molecule Ligands Targeting the HIV-1 Matrix Protein-RNA Binding Site

Alfadhli

McNett

Eccles

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

Analysis of Small Molecule Ligands Targeting the HIV-1 Matrix Protein-RNA Binding Site

Alfadhli

McNett

Eccles

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The founding members of this class are methylphenylurea compounds, such as CAP-1, which bind in a deep pocket in CA NTD , formed at the junction of helices 1, 2, 4, and 7 [120,121]. Interestingly, this pocket is not present in the static structure of free CA NTD , but rather is created when the conserved CA Phe32 residue swings out into solution.…”

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

412

422

View full text Add to dashboard Cite

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.

show abstract

“…In this respect, the actions of the MIANS and ANS compounds on NV maturation are similar to the action of the WIN compounds that inhibit picornavirus infectivity by binding to fully formed virus capsids and inhibiting dynamic quaternary breathing motions that are necessary for infection (20,25). Clearly, viral capsids can be targeted at several stages of the viral life cycle: by disrupting subunit polymerization (24,28,32,34) and by inhibiting dynamic capsid breathing (20,25), as well as by preventing maturation of the already-assembled capsid.…”

Section: Discussionmentioning

confidence: 95%

“…Whereas studies of disruption of virus function by capsiddirected compounds in other systems have demonstrated inhibition of proper assembly (24,28,32,34), in the case of the M-NV capsids the correct assembly has already been attained, and the interfering molecule does not break down the assembly. Instead, it appears that a later stage involving a large-scale conformational reorganization, required for maturation, has been inhibited by the introduction of the inhibitory compounds at interfaces.…”

Section: Discussionmentioning

confidence: 99%

“…Capsidtargeted compounds from the heteroaryldihydropyrimidine family also have been demonstrated to inhibit hepatitis B virus core particle formation (10); in vivo, this is accompanied by an increase in core protein degradation. Similarly, a recent study of human immunodeficiency virus type 1 assembly demonstrated that a small molecule (CAP-1) binds to the human immunodeficiency virus capsid protein and inhibits infectivity in a dose-dependent manner (28). The compound gives rise to abnormal core particles by interfering with interactions between capsid proteins that are critical for proper maturation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Small Compounds Targeted to Subunit Interfaces Arrest Maturation in a Nonenveloped, Icosahedral Animal Virus

Lee

Tang

Taylor

et al. 2004

J Virol

View full text Add to dashboard Cite

Nudaurelia capensis virus (NV) capsids were previously characterized in two morphological forms, a T‫,4؍‬ 485-Å-diameter round particle with large pores and a tightly sealed 395-Å icosahedrally shaped particle with the same quasi-symmetric surface lattice. The large particle converts to the smaller particle when the pH is lowered from 7.6 to 5, and this activates an autocatalytic cleavage of the viral subunit at residue 570. Here we report that both 1-anilino-8 naphthalene sulfonate (ANS) and the covalent attachment of the thiol-reactive fluorophore, maleimide-ANS (MIANS), inhibit the structural transition and proteolysis at the lower pH. When ANS is exhaustively washed from the particles, the maturation proceeds normally; however, MIANS-modified particles are still inhibited after the same washing treatment, indicating that covalent attachment targets MIANS to a critical location for inhibition. Characterization of the low-pH MIANS product by electron cryo-microscopy (cryo-EM) and image reconstruction demonstrated a morphology intermediate between the two forms previously characterized. A pseudoatomic model of the intermediate configuration was generated by rigid body refinement of the X-ray structure of the subunits (previously determined in the assembled capsid) into the cryo-EM density, allowing a quantitative description of the inhibited intermediate and a hypothesis for the mechanism of the inhibition.Protein capsids of many icosahedral viruses respond dynamically to environmental signals such as DNA or RNA packaging, receptor binding, and changes in pH and ionic composition. In so doing, they undergo conformational changes that involve the concerted reorganization of hundreds of protein subunits and nucleic acids. In many viruses, large-scale conformational transformations occur during assembly and maturation. Such transformations have been observed in several bacteriophages (7, 9, 11, 16, 19, 23, 30), herpesvirus (15, 33), and a single-stranded RNA insect virus (1, 4). Icosahedral virus particles with T numbers higher than 1 apparently do not always directly assemble into a highly stable form. Rather, capsid proteins initially organize into procapsid shells that place subunits into proper relative locations but with, in many cases, sparse interfacial contacts (4, 9, 16). These precursor particles are poised for reorganization into the stable mature particle when the proper signal is received by the protein or nucleo-protein aggregate (for examples, see references 4 and 9). Nudaurelia capensis virus (NV), an insect tetravirus, was the first single-stranded RNA animal virus for which threedimensional structures were determined for the procapsid and mature capsid conformations (4, 22). The procapsid structure was discovered for NV virus-like particles (VLPs) expressed in a recombinant baculovirus system. These particles contain heterologous cellular RNA in a ratio to protein that is similar to that of authentic virions (4). A cryo-electron microscopy (cryo-EM) reconstruction at 26 Å revealed a nearly spheri...

show abstract

Antiviral Inhibition of the HIV-1 Capsid Protein

Cited by 202 publications

References 38 publications

Analysis of Small Molecule Ligands Targeting the HIV-1 Matrix Protein-RNA Binding Site

Analysis of Small Molecule Ligands Targeting the HIV-1 Matrix Protein-RNA Binding Site

The structural biology of HIV assembly

Small Compounds Targeted to Subunit Interfaces Arrest Maturation in a Nonenveloped, Icosahedral Animal Virus

Contact Info

Product

Resources

About