Cell‐Free HIV‐1 Virucidal Action by Modified Peptide Triazole Inhibitors of Env gp120

Bastian, Arangassery Rosemary; Kantharaju,; McFadden, Karyn; Duffy, Caitlin; Rajagopal, Srivats; Contarino, Mark; Papazoglou, Elisabeth S.; Chaiken, Irwin M.

doi:10.1002/cmdc.201100177

Cited by 39 publications

(71 citation statements)

References 21 publications

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“…9 We further found that the terminal cysteine residue was required for luminal p24 release but was not essential for gp120 shedding, a phenotype displayed by non-sulfhydryl containing peptides ( 10 , HNG156, and 12 , UM15) and a sulfhydryl-blocked derivative ( 11 , KR13b). 8 Previously we synthesized a control peptide denoted KR13S, which contained a scrambled IXW pharmacophore (IWX).…”

Section: Resultsmentioning

confidence: 80%

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Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols

Bailey

Sundaram

et al. 2015

ACS Chem. Biol.

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We investigated the mode of action underlying lytic inactivation of HIV-1 virions by peptide triazole thiol (PTT), in particular the relationship between gp120 disulfides and the C-terminal cysteine-SH required for virolysis. Obligate PTT dimer obtained by PTT SH cross-linking and PTTs with serially truncated linkers between pharmacophore isoleucine–ferrocenyltriazole-proline–tryptophan and cysteine-SH were synthesized. PTT variants showed loss of lytic activity but not binding and infection inhibition upon SH blockade. A disproportionate loss of lysis activity vs binding and infection inhibition was observed upon linker truncation. Molecular docking of PTT onto gp120 argued that, with sufficient linker length, the peptide SH could approach and disrupt several alternative gp120 disulfides. Inhibition of lysis by gp120 mAb 2G12, which binds at the base of the V3 loop, as well as disulfide mutational effects, argued that PTT-induced disruption of the gp120 disulfide cluster at the base of the V3 loop is an important step in lytic inactivation of HIV-1. Further, PTT-induced lysis was enhanced after treating virus with reducing agents dithiothreitol and tris (2-carboxyethyl)phosphine. Overall, the results are consistent with the view that the binding of PTT positions the peptide SH group to interfere with conserved disulfides clustered proximal to the CD4 binding site in gp120, leading to disulfide exchange in gp120 and possibly gp41, rearrangement of the Env spike, and ultimately disruption of the viral membrane. The dependence of lysis activity on thiol–disulfide interaction may be related to intrinsic disulfide exchange susceptibility in gp120 that has been reported previously to play a role in HIV-1 cell infection.

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Section: Resultsmentioning

confidence: 80%

“…HIV-1 Env consists of 10 conserved disulfides, 9 of which are located within gp120 and the tenth in gp41. 9,15–17 We speculate that, in order to reach specific gp120 disulfides, a minimum distance between IXW and the free SH group is required.…”

Section: Resultsmentioning

confidence: 99%

Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols

Bailey

Sundaram

et al. 2015

ACS Chem. Biol.

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“…This class of compounds was found to induce shedding of gp120, thus inactivating the virus before cell encounter [9,10]. In addition, peptide triazole thiols (PTTs), PTs containing a free sulf-hydryl group (SH) on Cys at the C-terminus, were found to cause envelope disruption and p24 capsid protein release from the virus lumen [9,10]. The PTTs were initially made to conjugate to gold nanoparticles to form multivalent and consequently more potent inhibitors by providing the ability to interact with multiple Env proteins on single virions.…”

Section: Direct Virus Inactivation By Pts Discoveredmentioning

confidence: 99%

Peptide Triazole Inactivators of HIV-1: How Do They Work and What is Their Potential?

Chaiken

Rashad

2015

Future Med. Chem.

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“…We previously identified a peptide triazole (PT) class of entry inhibitors that binds to HIV-1 Env gp120 with nanomolar affinity, inhibits cell infection by a broad range of virus subtypes and inactivates virus before host cell encounter by triggering gp120 shedding (Bastian et al, 2013; Bastian et al, 2011; McFadden et al, 2012). The ability of PTs to inhibit both CD4 and co-receptor binding sites in gp120, and the virus-inactivation functions of this class of inhibitors, appear to derive from entrapment of Env gp120 in a conformationally-disrupted and functionally-inactivated state.…”

mentioning

confidence: 99%

“…The ability of PTs to inhibit both CD4 and co-receptor binding sites in gp120, and the virus-inactivation functions of this class of inhibitors, appear to derive from entrapment of Env gp120 in a conformationally-disrupted and functionally-inactivated state. Importantly, we recently found that peptide triazole thiols and a multivalent form of the PT thiol KR13 displayed on gold nanoparticles (AuNP-KR13) were able to disrupt the virus particles, causing leakage of the internal protein p24 (Bastian et al, 2013; Bastian et al, 2011). The Env-inactivating functions of KR13 and AuNP-KR13 rely on the ability to disrupt the intrinsically metastable Env gp120/gp41 complex on the virus surface (Bastian et al, 2013; Bastian et al, 2015).…”

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confidence: 99%

Targeting cell surface HIV-1 Env protein to suppress infectious virus formation

et al. 2017

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HIV-1 Env protein is essential for host cell entry, and targeting Env remains an important antiretroviral strategy. We previously found that a peptide triazole thiol KR13 and its gold nanoparticle conjugate AuNP-KR13 directly and irreversibly inactivate the virus by targeting the Env protein, leading to virus gp120 shedding, membrane disruption and p24 capsid protein release. Here, we examined the consequences of targeting cell-surface Env with the virus inactivators. We found that both agents led to formation of non-infectious virus from transiently transfected 293T cells. The budded non-infectious viruses lacked Env gp120 but contained gp41. Importantly, budded virions also retained the capsid protein p24, in stark contrast to p24 leakage from viruses directly treated by these agents and arguing that the agents led to deformed viruses by transforming the cells at a stage before virus budding. We found that the Env inactivators caused gp120 shedding from the transiently transfected 293T cells as well as non-producer CHO-K1-gp160 cells. Additionally, AuNP-KR13 was cytotoxic against the virus-producing 293T and CHO-K1-gp160 cells, but not untransfected 293T or unmodified CHO-K1 cells. The results obtained reinforce the argument that cell-surface HIV-1 Env is metastable, as on virus particles, and provides a conformationally vulnerable target for virus suppression and infectious cell inactivation.

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Cell‐Free HIV‐1 Virucidal Action by Modified Peptide Triazole Inhibitors of Env gp120

Cited by 39 publications

References 21 publications

Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols

Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV-1 by Peptide Triazole Thiols

Peptide Triazole Inactivators of HIV-1: How Do They Work and What is Their Potential?

Targeting cell surface HIV-1 Env protein to suppress infectious virus formation

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