Mandelic Acid Condensation Polymer: Novel Candidate Microbicide for Prevention of Human Immunodeficiency Virus and Herpes Simplex Virus Entry

Herold, Betsy C.; Scordi-Bello, Irini; Cheshenko, Natalia; Marcellino, Daniel; Dzuzelewski, M.; François, Fleur; Morin, Renaud; Casullo, Veronica Mas; Anderson, Robert A.; Chany, Calvin J.; Waller, Donald P.; Zaneveld, L. J. D.; Klotman, Mary E.

doi:10.1128/jvi.76.22.11236-11244.2002

Cited by 70 publications

(88 citation statements)

References 41 publications

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“…Little antiviral activity was observed when the target T cells were treated with PPCM and then washed to remove drug prior to viral exposure, suggesting that the drug needs to be present at the time of viral exposure. These data are consistent with earlier studies indi- cating that the drug primarily targets the virus and has greater antiviral activity against X4 than against R5 viruses (21).…”

Section: Resultssupporting

confidence: 82%

“…Prior studies have demonstrated that PPCM inhibits HSV infection primarily by binding to the viral envelope and inhibiting viral binding and entry (21). We have extended these in vitro observations and demonstrated that PPCM also blocks HSV infection of cervical explant cultures (Fig.…”

Section: Vol 82 2008 Ppcm Blocks Hiv and Prevents Genital Hsv 6579supporting

confidence: 57%

“…This compound was initially designated sulfuric acidmodified mandelic acid and has since been named PPCM by Yaso Biotechnologies, Inc., on the basis of further clarification of the chemical structure and synthesis (D. P. Waller, unpublished results). Although it has no sulfations or sulfonations, earlier studies indicated that this compound blocks the binding of HIV and HSV to cells by targeting the envelope glycoproteins gp120 and gB-2, respectively, and inhibits viral entry (21,47). The current studies were undertaken to further define the extent of anti-HIV activity of PPCM in cell and explant culture models and to evaluate the anti-HIV activity of PPCM combined in vitro with the candidate microbicide antiretroviral agents tenofovir (PMPA {9-[R-2-(phosphonylmethoxy)propyl]-adenine monohydrate}) (1) and UC-781 (2).…”

mentioning

confidence: 99%

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Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

Mesquita

Wilson

Manlow

et al. 2008

J Virol

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A structurally novel candidate microbicide, PPCM, which is formed from the reaction of D,L-mandelic acid with sulfuric acid, provides activity against human immunodeficiency virus (HIV) and herpes simplex virus (HSV) and is not cytotoxic. The objectives of the current studies were to comprehensively evaluate the activity of PPCM in cell and explant cultures, explore the possibility of combining PPCM with HIV-specific reverse transcriptase inhibitors, and evaluate the efficacy of a formulated gel against genital herpes in a murine model. PPCM inhibited infection by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical and endocervical tissue explants exposed to HIV-1 BaL in the presence of PPCM were protected (50% inhibitory concentrations [IC 50 ] of 3.9 g/ml for ectocervix and 3.1 g/ml for endocervix), and transfer of virus to target T cells via migratory cells was significantly impaired (IC 50 of 35.7 g/ml for ectocervix and 54.6 g/ml for endocervix). The drug also blocked infection by cell-associated virus. Combinations of PPCM with UC-781 or PMPA in vitro exhibited additive anti-HIV activity. PPCM was incorporated into stable, low-pH gel formulations at concentrations of 0.4% and 4%. Both gels prevented genital herpesvirus infection in mice, even when virus was introduced in human seminal plasma. The abilities of PPCM to inhibit primary HIV isolates, reduce infection by cell-associated virus, and transfer of HIV from migratory to T cells, combined with the complete protection provided by formulated gel against genital herpes, indicate that this drug is an excellent candidate for inclusion in a combination microbicide and would provide protection against both HIV and HSV.

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Section: Resultssupporting

confidence: 82%

Section: Vol 82 2008 Ppcm Blocks Hiv and Prevents Genital Hsv 6579supporting

confidence: 57%

mentioning

confidence: 99%

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Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

Mesquita

Wilson

Manlow

et al. 2008

J Virol

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“…HSV-2 recombinant glycoprotein B (gB2) was generated using the Bac-to-Bac system (Gibco) and purified by heparin-affinity chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining confirmed its purity (25). Anti-gB2 monoclonal antibody (1123) was purchased from the Goodwin Institute, Plantation, Fla.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that rabbit ␣ defensin NP-1 blocks HSV-2 infection at a step postbinding, but similar studies with human ␣ defensins have not been reported. To define the step(s) in HSV invasion that was blocked by retrocyclin 2 and HNPs 1 to 3 (25), kinetic assays were performed as previously described. CaSki cells were cooled to 4°C and exposed to virus for 3 h to allow viral attachment.…”

Section: Vol 78 2004 Defensins Protect Cells From Hsv Infection 5149mentioning

confidence: 99%

θ Defensins Protect Cells from Infection by Herpes Simplex Virus by Inhibiting Viral Adhesion and Entry

Yasin¹,

Wang

Pang³

et al. 2004

J Virol

224

216

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We tested the ability of 20 synthetic defensins to protect cells from infection by type 1 and type 2 herpes simplex viruses (HSV-1 and -2, respectively). The peptides included rhesus defensins (RTDs) 1 to 3, originally isolated from rhesus macaque leukocytes, and three peptides (retrocyclins 1 to 3) whose sequences were inferred from human -defensin (DEFT) pseudogenes. We also tested 14 retrocyclin analogues, including the retro, enantio, and retroenantio forms of retrocyclin 1. Retrocyclins 1 and 2 and RTD 3 protected cervical epithelial cells from infection by both HSV serotypes, but only retrocyclin 2 did so without causing cytotoxicity or requiring preincubation with the virus. Surface plasmon resonance studies revealed that retrocyclin 2 bound to immobilized HSV-2 glycoprotein B (gB2) with high affinity (K d , 13.3 nM) and that it did not bind to enzymatically deglycosylated gB2. Temperature shift experiments indicated that retrocyclin 2 and human ␣ defensins human neutrophil peptide 1 (HNP 1) to HNP 3 protected human cells from HSV-2 by different mechanisms. Retrocyclin 2 blocked viral attachment, and its addition during the binding or penetration phases of HSV-2 infection markedly diminished nuclear translocation of VP16 and expression of ICP4. In contrast, HNPs 1 to 3 had little effect on binding but reduced both VP16 transport and ICP4 expression if added during the postbinding (penetration) period. We recently reported that defensins are miniature lectins that bind gp120 of human immunodeficiency virus type 1 (HIV-1) with high affinity and inhibit the entry of R5 and X4 isolates of HIV-1. Given its small size (18 residues), minimal cytotoxicity, lack of activity against vaginal lactobacilli, and effectiveness against both HSV-2 and HIV-1, retrocyclin 2 provides an intriguing prototype for future topical microbicide development.The worldwide AIDS epidemic has intensified interest in identifying naturally occurring antiviral molecules (5,29,34,57). Certain rabbit and human ␣ defensins were shown to protect cells from infection by herpes simplex virus type 1 (HSV-1) and HSV-2 almost 20 years ago (17,30), and more recent studies indicated that rabbit ␣ defensin NP-1 blocks HSV infection at a very early stage (46). Even adenoviruses, which are nonenveloped, are susceptible to ␣ defensins (3, 21), although the mechanism of this effect is unknown. In vitro, human ␣ defensins human neutrophil peptide 1 (HNP 1) to HNP 3 can protect cells from infection by human immunodeficiency virus type 1 (HIV-1), and release of these defensins from the ␣, ␤ CD8-positive T cells of HIV-infected subjects may (60) or may not (11) correlate with their long-term clinical stability.Defensin peptides belonging to three subfamilies, designated ␣, ␤, and defensins, have been identified in leukocytes and other cells of humans or nonhuman primates. ␣ defensins contain 29 to 35 residues and are produced as ϳ100-residue prepropeptides (16). Human neutrophils (polymorphonuclear leukocytes) contain four ␣ defensins, called HNPs 1, 2, 3, an...

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Versatile Photochemical Surface Modification of Biopolyester Microfibrous Scaffolds with Photogenerated Silver Nanoparticles for Antibacterial Activity

Versace¹,

Ramier²,

Grande³

et al. 2013

Adv Healthcare Materials

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A straightforward and versatile method for immobilizing macromolecules and silver nanoparticles on the surface of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) electrospun fibers is developed with the objective of designing a new functional material having significant antibacterial activity. The approach relies on a two-step procedure: UV photografting of poly(methacrylic acid) (PMAA) on the surface of PHBHV fibers according to a "grafting from" method, and complexation of in situ photogenerated silver nanoparticles (Ag NPs) by carboxyl groups from tethered PMAA chains. The photografting process is conducted through a photoinduced free-radical process employing a ketone-based photoinitiator in aqueous medium. Under appropriate conditions, the photogenerated radicals abstract hydrogen atoms from the PHBHV backbone, thus initiating the UV-mediated photopolymerization of MAA from the PHBHV microfibrous surface. The photochemical mechanism of the ketone photolysis is entirely described by the electron spin resonance/spin-trapping technique, and the modified PHBHV microfibrous scaffold is extensively characterized by ATR-FTIR spectroscopy, water contact-angle measurements, and mercury intrusion porosimetry. In a second step, the in situ synthesis of Ag NPs within the microfibrous scaffold is implemented by photoreduction reaction in the presence of both a silver precursor and a photosensitizer. The photoinduced formation of Ag NPs is confirmed by UV spectrophotometry and XPS analysis. SEM and TEM experiments confirm the formation and dispersion of Ag NPs on the surface of the modified fibers. Finally, a primary investigation is conducted to support the antibacterial activity of the new functionalized biomaterial against Staphylococcus aureus and Escherichia coli.

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Mandelic Acid Condensation Polymer: Novel Candidate Microbicide for Prevention of Human Immunodeficiency Virus and Herpes Simplex Virus Entry

Cited by 70 publications

References 41 publications

Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

Candidate Microbicide PPCM Blocks Human Immunodeficiency Virus Type 1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

θ Defensins Protect Cells from Infection by Herpes Simplex Virus by Inhibiting Viral Adhesion and Entry

Versatile Photochemical Surface Modification of Biopolyester Microfibrous Scaffolds with Photogenerated Silver Nanoparticles for Antibacterial Activity

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