Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses

Gong, Edwin Yunhao; Matthews, Barry; McCarthy, Tom D.; Chu, Jianhua; Holan, G.; Raff, J. W.; Sacks, Stephen L.

doi:10.1016/j.antiviral.2005.08.004

Cited by 80 publications

(65 citation statements)

References 13 publications

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“…Indeed, in vitro analysis has revealed that sulfonated and carboxylated polylysine dendrimers effectively block the HSV-1 and -2 infection of cells and non-primate animal studies have shown that they were able to protect animals against an intravaginal HSV-2 challenge (Bourne et al, 2000;Bernstein et al, 2003;Gong et al, 2005). However, in addition to inhibiting the HSV attachment, the sulfonate ddendrimers were also shown to act at a post-entry level by apparently inhibiting HSV DNA synthesis, which suggests that they could be used not only for prevention of HSV infection but also as inhibitors of viral replication (Gong et al, 2005). Sulfonated polylysine dendrimers, similar to those selected against HSV, were also found to inhibit HIV-1 infection and block vaginal SHIV (chimeric simian-human immunodeficiency-1 virus) transmission in pigtailed macaques Rupp et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection by blocking virus binding to cell surface heparan sulfate

et al. 2010

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Dendrimers are hyperbranched synthetic well-defined molecules with a number of potential applications, especially in relation to the need for new antiviral agents. One subclass of dendrimers are peptide derivatized-dendrimers which consist of a peptidyl branching core and covalently attached surface peptide functional units. Few studies have addressed the potential uses of peptide dendrimers as direct-acting antiviral agents. Here, we report on the ability of two peptide dendrimers, SB105 and SB105_A10, to directly and almost completely inhibit human cytomegalovirus (HCMV) replication in both primary fibroblasts and endothelial cells; the agents were also found to inhibit murine CMV replication, whereas they were not able to inhibit the adenovirus or vesicular stomatitis virus. The peptide dendrimers prevented adsorption of the HCMV to cells at 4° C, whereas SB104, a dendrimer with a different amino acid sequence within the functional group and minimal anticytomegaloviral activity, was ineffective in blocking HCMV attachment. In effect, SB105_A10 bound to human cells through an interaction with cell surface heparan sulfate and thereby blocked virion attachment to target cells. These results indicate that the SB105 and SB105_A10 dendrimers could provide a useful starting point for the development of novel molecules to block HCMV infection.

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Section: Discussionmentioning

confidence: 99%

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection by blocking virus binding to cell surface heparan sulfate

et al. 2010

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“…SPL7013 is the active ingredient of a polylysine dendrimer. SPL7013 is a topical antimicrobial agent that was shown to be effective against herpes simplex virus (HSV-1 and HSV-2) 44 and human immunodeficiency virus (HIV) in vitro. 45 Unformulated SPL7013 was also employed in animal model studies.…”

Section: Therapeutic Applications Antibacterial Agentsmentioning

confidence: 99%

Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications

Kalomiraki¹,

Thermos²,

Chaniotakis³

2015

IJN

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Abstract:Dendrimers are large polymeric structures with nanosize dimensions (1-10 nm) and unique physicochemical properties. The major advantage of dendrimers compared with linear polymers is their spherical-shaped structure. During synthesis, the size and shape of the dendrimer can be customized and controlled, so the finished macromolecule will have a specific "architecture" and terminal groups. These characteristics will determine its suitability for drug delivery, diagnostic imaging, and as a genetic material carrier. This review will focus initially on the unique properties of dendrimers and their use in biomedical applications, as antibacterial, antitumor, and diagnostic agents. Subsequently, emphasis will be given to their use in drug delivery for ocular diseases.

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Section: Cells and Virusesmentioning

confidence: 99%

“…16 HSV-2 strain 333 isolate was provided by Dr A. Alcamí (Severo Ochoa Centre for Molecular Biology (CBMSO), Spain). Stock of HSV-2 was prepared and titrated by plaque assay 16 and stored at −80°C. Human cell lines have been used following the principles outlined in the Declaration of Helsinki, and no ethics committee approval was required for this set of experiments.…”

Section: Cells and Virusesmentioning

confidence: 99%

Prevention of vaginal and rectal herpes simplex virus type 2 transmission in mice: mechanism of antiviral action

Ceña-Díez¹,

Vacas-Córdoba²,

García-Broncano³

et al. 2016

IJN

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Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH–gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.

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Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses

Cited by 80 publications

References 13 publications

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection by blocking virus binding to cell surface heparan sulfate

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection by blocking virus binding to cell surface heparan sulfate

Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications

Prevention of vaginal and rectal herpes simplex virus type 2 transmission in mice: mechanism of antiviral action

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