Synergistic activity of carbosilane dendrimers in combination with maraviroc against HIV in vitro

Córdoba, Enrique Vacas; Arnáiz, Eduardo; Mata, F. Javier de la; Gómez, Rafael; Leal, Manuel; Pion, Marjorie; Muñoz‐Fernández, María Ángeles

doi:10.1097/qad.0b013e328361fa4a

Cited by 29 publications

(19 citation statements)

References 17 publications

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“…8,9,14,15 Eight dendrimers were dissolved in distilled water in a final concentration of 1 mM. Dilutions to µM range were generated in distilled water from the stock.…”

Section: Materials and Methods Compoundsmentioning

confidence: 99%

“…14,38 To potentially limit the selection of resistant strains that may compromise the treatment options and improve the efficacy of current antivirals, the use of combinations of different agents could be an interesting approach. 8,9,14,17 Our dendrimers have shown an additive or synergistic profile when combined with ACV or TFV. The obtained synergy can be due to the fact that the dendrimers and ACV or TFV act at different steps in the viral cycle.…”

mentioning

confidence: 86%

“…[7][8][9]17 However, their ability to inhibit other sexually transmitted infections is unknown. In this work, antiviral activity against HSV-2 of eight dendrimers, which previously showed high anti-HIV activity were researched.…”

Section: Screening Of Polyanionic Carbosilane Dendrimers Antiviral Acmentioning

confidence: 99%

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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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“…8,9,14,15 Eight dendrimers were dissolved in distilled water in a final concentration of 1 mM. Dilutions to µM range were generated in distilled water from the stock.…”

Section: Materials and Methods Compoundsmentioning

confidence: 99%

mentioning

confidence: 86%

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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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“…26 The TZM-bl cells were cultured as described. 25 Peripheral blood mononuclear cells (PBMCs) were isolated using a standard Ficoll gradient from buffy coats (Rafer, Spain) and were cultured as previously described. …”

Section: Materials and Methods Cells And Cell Culturementioning

confidence: 99%

“…24 Moreover, we have already shown that combination of maraviroc and the polyanionic carbosilane dendrimers G3-S16 and G2-NF16 increased their antiviral potency, both additively and synergistically, against CCR5-tropic HIV; the main viral strain involved in primary infection during sexual transmission, and dual tropic HIV-1 isolates. 25 In this work, we studied the combinatorial activity profile of these polyanionic carbosilane dendrimers (G3-S16 and G2-NF16; Figure 1) in combination with other ARVs, such as zidovudine (AZT), efavirenz (EFV), and TFV, International Journal of Nanomedicine 2014:9 submit your manuscript | www.dovepress.com…”

Section: Introductionmentioning

confidence: 99%

Enhanced activity of carbosilane dendrimers against HIV when combined with reverse transcriptase inhibitor drugs: searching for more potent microbicides

Vacas-Córdoba¹,

Galán

Mata

et al. 2014

IJN

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Self-administered topical microbicides or oral preexposure prophylaxis could be very helpful tools for all risk groups to decrease the human immunodeficiency virus (HIV)-1 infection rates. Up until now, antiretrovirals (ARVs) have been the most advanced microbicide candidates. Nevertheless, the majority of clinical trials has failed in HIV-1 patients. Nanotechnology offers suitable approaches to develop novel antiviral agents. Thereby, new nanosystems, such as carbosilane dendrimers, have been shown to be safe and effective compounds against HIV with great potential as topical microbicides. In addition, because most of the attempts to develop effective topical microbicides were unsuccessful, combinatorial strategies could be a valid approach when designing new microbicides. We evaluated various combinations of anionic carbosilane dendrimers with sulfated (G3-S16) and naphthyl sulfonated (G2-NF16) ended groups with different ARVs against HIV-1 infection. The G3-S16 and G2-NF16 dendrimers showed a synergistic or additive activity profile with zidovudine, efavirenz, and tenofovir in the majority of the combinations tested against the X4 and R5 tropic HIV-1 in cell lines, as well as in human primary cells. Therefore, the combination of ARVs and polyanionic carbosilane dendrimers enhances the antiviral potency of the individual compounds, and our findings support further clinical research on combinational approaches as potential microbicides to block the sexual transmission of HIV-1.

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The Importance of Dendrimers in Pharmaceutical Applications

Brunetti

Martinelli

Strumia

2015

Handbook of Polymers for Pharmaceutical Technologies

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Synergistic activity of carbosilane dendrimers in combination with maraviroc against HIV in vitro

Abstract: The evaluated two-drug combinations increase their antiviral potency supporting further clinical investigations to develop combinatorial formulated topical microbicides to fight against the worldwide HIV spread.

Cited by 29 publications

References 17 publications

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

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

Enhanced activity of carbosilane dendrimers against HIV when combined with reverse transcriptase inhibitor drugs: searching for more potent microbicides

The Importance of Dendrimers in Pharmaceutical Applications

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