Oligovalent Amyloid-Binding Agents Reduce SEVI-Mediated Enhancement of HIV-1 Infection

Capule, Christina C.; Brown, C. Mackenzie; Olsen, Joanna S.; Dewhurst, Stephen; Yang, Jerry

doi:10.1021/ja210931b

Cited by 37 publications

(65 citation statements)

References 47 publications

(74 reference statements)

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“…For example, as semen is the major vector for sexual transmission of HIV (Royce et al, 1997), the presence of SEVI in seminal fluid could increase the rate of transmission and thus offer a target for intervention. In fact, several SEVI antagonists have already been described (Capule et al, 2012; Hauber et al, 2009; Olsen et al, 2010; Roan et al, 2010). However, transmission across the mucosal barrier in vivo is much more complex than infection of cell cultures and cationic bridging might have little impact.…”

Section: Introductionmentioning

confidence: 99%

No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts

Dis¹,

Moore²,

Lavender³

et al. 2016

Virology

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Amyloid fibrils from semen-derived peptide (SEVI) enhance HIV-1 infectivity in vitro but the ability of SEVI to mediate enhancement of HIV infection in vivo has not been tested. In this study we used immunodeficient mice reconstituted with human immune systems to test for in vivo enhancement of HIV-1 transmission. This mouse model supports mucosal transmission of HIV-1 via the intrarectal route leading to productive infection. In separate experiments with humanized mouse cohorts reconstituted with two different donor immune systems, high dose HIV-1JR-CSF that had been incubated with SEVI amyloid fibrils at physiologically relevant concentrations did not show an increased incidence of infection compared to controls. In addition, SEVI failed to enhance rectal transmission with a reduced concentration of HIV-1. Although we confirmed potent SEVI-mediated enhancement of HIV infectivity in vitro, this model showed no evidence that it plays a role in the much more complex situation of in vivo transmission.

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Section: Introductionmentioning

confidence: 99%

No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts

Dis¹,

Moore²,

Lavender³

et al. 2016

Virology

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“…Additionally, these binding studies support our hypothesis that the PEG 3 linker of 3 was successful in minimizing the steric effects of the bulky 5/6-carboxyrhodamine 110 fluorescent tag on compound 4, consistent with published reports demonstrating the tolerance of its high-affinity binding characteristics to the addition of sterically bulky groups and PEG linkers. 29, 30, 33 Thus, the clickable PiB derivative 3 exhibits potent binding to aggregated Aβ, and is an ideal platform from which to develop novel high-affinity covalent conjugates of PiB.…”

Section: Resultsmentioning

confidence: 99%

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

et al. 2017

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The benzothiazole-aniline derivative Pittsburgh Compound B (PiB) is the prototypical amyloid affinity probe developed for the in vivo positron emission tomography (PET) detection of amyloid beta (Aβ) deposits in Alzheimer’s disease (AD). Specific high-affinity binding sites for PiB have been found to vary among AD cases with comparable Aβ load, and they are virtually absent on human-sequence Aβ deposits in animal models, none of which develop the full phenotype of AD. PiB thus could be an informative probe for studying the pathobiology of Aβ, but little is known about the localization of PiB binding at the molecular or structural level. By functionalizing the 6-hydroxy position of PiB with a PEG3 spacer and a terminal alkyne (propargyl) moiety, we have developed a clickable PiB compound that was derivatized with commercially available azide-labeled fluorophores or affinity-tags using copper-catalyzed azide-alkyne cycloaddition reactions, commonly referred to as “click” chemistry. We have determined that both the clickable PiB derivative and its fluorescently-labeled conjugate have low nanomolar binding affinities for synthetic Aβ aggregates. Furthermore, the fluorescent-PiB conjugate can effectively bind Aβ aggregates in human AD brain homogenates and tissue sections. By covalently coupling PiB to magnetic beads, Aβ aggregates were also affinity-captured from AD brain extracts. Thus, the clickable PiB derivative described herein can be used to generate a wide variety of covalent conjugates, with applications including the fluorescence detection of Aβ, the ultrastructural localization of PiB binding, and the affinity capture and structural characterization of Aβ and other co-factors from AD brains.

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“…20,21 We showed that while the monomeric BTA molecules were effective at inhibiting HIV infection, oligomeric versions of BTA exhibited improved activity for inhibiting SEVI-mediated HIV infection. These BTA oligomers also exhibited enhanced binding to the SEVI amyloid putatively through multivalent binding.…”

mentioning

confidence: 94%

Inhibition of the Enhancement of Infection of Human Immunodeficiency Virus by Semen-Derived Enhancer of Virus Infection Using Amyloid-Targeting Polymeric Nanoparticles

et al. 2015

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The semen-derived enhancer of virus infection (SEVI) is natural amyloid material that has been shown to substantially increase viral attachment and infectivity of HIV in cells. We previously reported that synthetic monomeric and oligomeric amyloid-targeting molecules could form protein-resistive coatings on SEVI and inhibit SEVI- and semen-mediated enhancement of HIV infectivity. While oligomeric amyloid-binding compounds showed substantial improvement in apparent binding to SEVI compared to monomeric compounds, we observed only a modest correlation between apparent binding to SEVI and activity for reducing SEVI-mediated HIV infection. Here, we synthesized amyloid-binding polyacrylate-based polymers and polymeric nanoparticles of comparable size to HIV virus particles (~150 nm) to assess the effect of sterics on the inhibition of SEVI-mediated enhancement of HIV infectivity. We show that these polymeric materials exhibit excellent capability to reduce SEVI-mediated enhancement of HIV infection, with the nanoparticles exhibiting the greatest activity (IC50 value of ~4 μg/mL, or 59 nM based on polymer) of any SEVI-neutralizing agent reported to date. The results support that the improved activity of these nanomaterials is likely due to their increased size (diameters = 80-200 nm) compared to amyloid-targeting small molecules, and that steric interactions may play as important a role as binding affinity in inhibiting viral infection mediated by SEVI amyloids. In contrast to the previously reported SEVI neutralizing, amyloid-targeting molecules (which required concentrations at least 100-fold above the Kd to observe activity), the approximate 1:1 ratio of apparent Kd to IC50 for activity of these polymeric materials, suggests the majority of polymer molecules that are bound to SEVI contribute to the inhibition of HIV infectivity enhanced by SEVI. Such size-related effects on physical inhibition of protein-protein interactions may open further opportunities for the use of targeted nanomaterials in disease intervention.

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Oligovalent Amyloid-Binding Agents Reduce SEVI-Mediated Enhancement of HIV-1 Infection

Cited by 37 publications

References 47 publications

No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts

No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

Inhibition of the Enhancement of Infection of Human Immunodeficiency Virus by Semen-Derived Enhancer of Virus Infection Using Amyloid-Targeting Polymeric Nanoparticles

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