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Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

2015-07Journal article Open access
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dc.contributor.authorBriz, Verónica
dc.contributor.authorSepúlveda-Crespo, Daniel
dc.contributor.authorDiniz, Ana Rita
dc.contributor.authorBorrego, Pedro
dc.contributor.authorRodes, Berta
dc.contributor.authorJavier de la Mata, Francisco
dc.contributor.authorGómez, Rafael
dc.contributor.authorTaveira, Nuno
dc.contributor.authorMuñoz-Fernández, Mª Ángeles
dc.date.accessioned2016-10-12T08:53:14Z
dc.date.available2016-10-12T08:53:14Z
dc.date.issued2015-07
dc.descriptionThis is the author’s version of a work that was accepted for publication in Nanoscale.pt_PT
dc.description.abstract"The development of topical microbicide formulations for vaginal delivery to prevent HIV-2 sexual transmission is urgently needed. Second- and third-generation polyanionic carbosilane dendrimers with a silicon atom core and 16 sulfonate (G2-S16), napthylsulfonate (G2-NS16) and sulphate (G3-Sh16) end-groups have shown potent and broad-spectrum anti-HIV-1 activity. However, their antiviral activity against HIV-2 and mode of action have not been probed. Cytotoxicity, anti-HIV-2, anti-sperm and antimicrobial activities of dendrimers were determined. Analysis of combined effects of triple combinations with tenofovir and raltegravir was performed by using CalcuSyn software. We also assessed the mode of antiviral action on the inhibition of HIV-2 infection through a panel of different in vitro antiviral assays: attachment, internalization in PBMCs, inactivation and cell-based fusion. Vaginal irritation and histological analysis in female BALB/c mice were evaluated. Our results suggest that G2-S16, G2-NS16 and G3-Sh16 exert anti-HIV-2 activity at an early stage of viral replication inactivating the virus, inhibiting cell-to-cell HIV-2 transmission, and blocking the binding of gp120 to CD4, and the HIV-2 entry. Triple combinations with tenofovir and raltegravir increased the anti-HIV-2 activity, consistent with synergistic interactions (CIwt: 0.33–0.66). No vaginal irritation was detected in BALB/c mice after two consecutive applications for 2 days with 3% G2-S16. Our results have clearly shown that G2-S16, G2-NS16 and G3-Sh16 have high potency against HIV-2 infection. The modes of action confirm their multifactorial and non-specific ability, suggesting that these dendrimers deserve further studies as potential candidate microbicides to prevent vaginal/rectal HIV-1/HIV-2 transmission in humans."pt_PT
dc.identifier.citationNanoscale. 2015 Sep 21;7(35):14669-83. doi: 10.1039/c5nr03644ept_PT
dc.identifier.doi10.1039/C5NR03644Ept_PT
dc.identifier.issn2040-3372
dc.identifier.urihttp://hdl.handle.net/10400.26/15083
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherRoyal Society of Chemistrypt_PT
dc.relationDEVELOPMENT AND PRE-CLINICAL EVALUATION OF A NEW MICROBICIDE GEL FOR THE PREVENTION OF HIV-1 AND HIV-2 INFECTION
dc.relation.publisherversionhttp://dx.doi.org/10.1039/c5nr03644ept_PT
dc.subjectHIV-2 preventionpt_PT
dc.subjectIn vivo micept_PT
dc.subjectMicrobicidespt_PT
dc.subjectMode of actionpt_PT
dc.subjectPolyanionic carbosilane dendrimerspt_PT
dc.titleDevelopment of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicidespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDEVELOPMENT AND PRE-CLINICAL EVALUATION OF A NEW MICROBICIDE GEL FOR THE PREVENTION OF HIV-1 AND HIV-2 INFECTION
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/VIH%2FSAU%2F0029%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F89140%2F2012/PT
oaire.citation.endPage14683pt_PT
oaire.citation.startPage14669pt_PT
oaire.citation.titleNanoscalept_PT
oaire.citation.volume7pt_PT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicatione63cde82-fa32-4aed-90e7-c9443427f2e1
relation.isProjectOfPublicationeb28382d-1ebf-4ed8-8974-0d1d07f67887
relation.isProjectOfPublication.latestForDiscoverye63cde82-fa32-4aed-90e7-c9443427f2e1

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