Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

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Abstract

Background

Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.

Methods and Findings

Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.

Conclusions

Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel® and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

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Most cited references 48

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Molecular architecture of native HIV-1 gp120 trimers.

Jun Liu, Alberto Bartesaghi, Mario J. Borgnia … (2008)

The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.

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Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies.

Judith R Glynn, Olivia E. Freeman, Keith R. Hayes … (2006)

To estimate the sex-specific effect of herpes simplex virus type 2 (HSV-2) on the acquisition of HIV infection. The increased number of longitudinal studies available since the last meta-analysis was published allows for the calculation of age- and sexual behaviour-adjusted relative risks (RR) separately for men and women. Systematic review and meta-analysis of longitudinal studies. PubMed, Embase and relevant conference abstracts were systematically searched to identify longitudinal studies in which the relative timing of HSV-2 infection and HIV infection could be established. Where necessary, authors were contacted for separate estimates in men and women, adjusted for age and a measure of sexual behaviour. Summary adjusted RR were calculated using random-effects meta-analyses where appropriate. Studies on recent HSV-2 incidence as a risk factor for HIV acquisition were also collated. Of 19 eligible studies identified, 18 adjusted for age and at least one measure of sexual behaviour after author contact. Among these, HSV-2 seropositivity was a statistically significant risk factor for HIV acquisition in general population studies of men [summary adjusted RR, 2.7; 95% confidence interval (CI), 1.9-3.9] and women (RR, 3.1; 95% CI, 1.7-5.6), and among men who have sex with men (RR, 1.7; 95% CI, 1.2-2.4). The effect in high-risk women showed significant heterogeneity, with no overall evidence of an association. Prevalent HSV-2 infection is associated with a three-fold increased risk of HIV acquisition among both men and women in the general population, suggesting that, in areas of high HSV-2 prevalence, a high proportion of HIV is attributable to HSV-2.

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Structure of a V3-containing HIV-1 gp120 core.

Chih-chin Huang, Min Tang, Mei-Yun Zhang … (2005)

The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2010

Publication date (Electronic): 23 August 2010

Volume: 5

Issue: 8

Electronic Location Identifier: e12309

Affiliations

[1 ]Centres for Virology and Immunology, Burnet Institute, Melbourne, Victoria, Australia

[2 ]Starpharma Pty Ltd, Melbourne, Victoria, Australia

[3 ]Faculty of Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia

[4 ]Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

[5 ]Department of Microbiology, Monash University, Clayton, Victoria, Australia

[6 ]Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia

[7 ]Department of Medicine, Monash University, Melbourne, Victoria, Australia

[8 ]Department of Surgery (Austin Health), University of Melbourne, Heidelberg, Victoria, Australia

[9 ]Department of Immunology, Monash University, Melbourne, Victoria, Australia

[10 ]Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, United States of America

University of Pittsburgh, United States of America

Author notes

* E-mail: gildat@ 123456burnet.edu.au

Conceived and designed the experiments: DT SAH AJ GK SW TM RC GT. Performed the experiments: DT SAH AJ JS KM JL MZ PK MPG GK RC. Analyzed the data: DT SAH AJ JS KM JL MZ GK TM PR RC GT. Contributed reagents/materials/analysis tools: TM PRG PR JRP GRL. Wrote the paper: SAH JS SS GK SW TM PRG PR RC JRP GRL GT.

Article

Publisher ID: 10-PONE-RA-20007R1

DOI: 10.1371/journal.pone.0012309

PMC ID: 2925893

PubMed ID: 20808791

SO-VID: 9a29aba9-7390-4c01-b3ee-efcdd04d99e5

Copyright © Tyssen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 19 June 2010

Date accepted : 25 July 2010

Page count

Pages: 15

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Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

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Abstract

Background

Methods and Findings

Conclusions

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PLOS: COVID-19 pandemic

Most cited references 48

Molecular architecture of native HIV-1 gp120 trimers.

Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies.

Structure of a V3-containing HIV-1 gp120 core.

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Cited by 52

Most referenced authors 1,383