Abstract:Microbicides are women-controlled prophylactics for sexually transmitted infections. The most important class of microbicides target HIV-1 and contain antiviral agents formulated for topical vaginal delivery. Identification of new viral entry inhibitors that target the HIV-1 envelope is important because they can inactivate HIV-1 in the vaginal lumen before virions can come in contact with CD4+ cells in the vaginal mucosa. Carbohydrate binding agents (CBAs) demonstrate the ability to act as entry inhibitors due to their ability to bind to glycans and prevent gp120 binding to CD4+ cells. However, as proteins they present significant challenges in regard to economical production and formulation for resource-poor environments. We have synthesized water-soluble polymer CBAs that contain multiple benzoboroxole moieties. A benzoboroxole-functionalized monomer was synthesized and incorporated into linear oligomers with 2-hydroxypropylmethacrylamide (HPMAm) at different feed ratios using free radical polymerization. The benzoboroxole small molecule analogue demonstrated weak affinity for HIV-1BaL gp120 by SPR; however, the 25 mol % functionalized benzoboroxole oligomer demonstrated a 10-fold decrease in the K D for gp120, suggesting an increased avidity for the multivalent polymer construct. High molecular weight polymers functionalized with 25, 50, and 75 mol % benzoboroxole were synthesized and tested for their ability to neutralize HIV-1 entry for two HIV-1 clades and both R5 and X4 coreceptor tropism. All three polymers demonstrated activity against all viral strains tested with EC 50 s that decrease from 15000 nM (1500 µg mL -1 ) for the 25 mol % functionalized polymers to 11 nM (1 µg mL -1 ) for the 75 mol % benzoboroxole-functionalized polymers. These polymers exhibited minimal cytotoxicity after 24 h exposure to a human vaginal cell line.

Materials that respond to physiological stimuli are important in developing advanced biomaterials for modern therapies. The reversibility of covalent crosslinks formed by phenylboronate (PBA) and salicylhydroxamate (SHA) has been exploited to provide a pH‐responsive gel for application to the vaginal tract. Dynamic rheology reveals that the gel frequency‐dependent viscoelastic properties are modulated by pH. At pH 4.8 the viscous component dominates throughout most of the frequency range. As the pH increases, the characteristic relaxation time continues to increase while the G′Plateau levels off above pH 6. At pH 7.5, the elastic component dominates throughout the frequency sweep and is predominately independent of frequency. Particle tracking assesses the transport of both fluorescently labeled HIV‐1 and 100‐nm latex particles in the PBA–SHA crosslinked gel as a function of pH. At pH 4.8 the ensemble‐averaged mean squared displacement at lag times greater than three seconds reveals that transport of the HIV‐1 and 100‐nm particles becomes significantly impeded by the matrix, exhibiting diffusion coefficients less than 0.0002 µm2 s−1. This pH‐responsive gel thus displays properties that have the potential to significantly reduce the transport of HIV‐1 to susceptible tissues and thus prevent the first stage of male‐to‐female transmission of HIV‐1.

Purpose To examine the longitudinal changes in the epithelial topography of the cervix in healthy young women; and to determine the sociodemographic, behavioral, and biological factors associated with the rate of cervical epithelial maturation. Methods Healthy young women were enrolled (10/00-9/02) as part of a larger study of human papillomavirus (HPV). At interval visits, interviews, infection testing, and colpophotography (3% acetic acid; 10X,16X magnifications) were performed. Areas of total cervical face and cervical immaturity, defined as columnar and early squamous metaplasia, were quantitatively measured using computerized planimetry. Cervical immaturity was expressed as percentage of total cervical face. This analysis includes the first consecutive 145 women with greater than 10% immaturity at baseline. The rate of cervical maturation was defined as change in percent-immaturity. Predictors included sociodemographics, sexual behaviors, and infections. Data analyses included multivariate generalized linear models with repeated measures. Results The baseline mean age was 17.8 years. Colpophotographs were available from 815 total visits, representing 2.7 years mean follow-up per woman and 5.9 month mean intervals. Women began the study with a median of 39% immaturity and ended with 8% immaturity. After adjusting for time and baseline percent-immaturity, an increased rate of cervical maturation was associated with oral contraceptive pill use (parameter estimate −0.023, p=0.04) and smoking (−0.039, p=0.01). Conclusions Cervical maturation was documented during relatively short time periods for the vast majority of these women. Oral contraceptive pills and smoking may accelerate the maturational process, representing increased cell proliferation and thus a possible greater vulnerability to HPV.

2-Mercapto-1-methylimidazole (mmim) forms complexes with organic iodides, 1,4-diiodotetrafluorobenzene (p-F4DIB), tetraiodoethylene (TIE), and 1,2-diiodotetrafluorobenzene (o-F4DIB), in which there are remarkably similar N−H···S hydrogen bonding and S···I halogen bonding patterns. Extended chains of alternating donor (mmim) and acceptor (p-F4DIB and TIE) molecules are formed through divalent I···S···I interactions. These chains are joined into double strands through N−H···S interactions that link two mmim molecules into a dimer. In the third complex, N−H···S bound dimers are linked into infinite chains through S···I interactions involving a pair of o-F4DIB molecules. Thermal analysis indicates that decomposition in both of the F4DIB complexes proceeds through total loss of acceptor, while decomposition of the TIE complex involves a combination of acceptor loss and acceptor reaction. Melting in the o-F4DIB complexes appears to be preceded by a solid-state rearrangement or premelting phenomenon that is not observed in the other two complexes. Crystal data for mmim· p-F4DIB:  monoclinic space group, C2/c (no. 15), a = 26.915(3) Å, b = 7.9216(6) Å, c = 14.2630(4) Å, β = 105.618(1)°, V = 2928.7(4) Å3, Z = 8, ρcalc = 2.34 g/cm3. Crystal data for mmim·TIE:  monoclinic space group, C2/c (no. 15), a = 20.1789(12) Å, b = 10.7824(10) Å, c = 14.5072(2) Å, β = 118.767(1)°, V = 2766.9(3) Å3, Z = 8, ρcalc = 3.10 g/cm3. Crystal data for mmim· o-F4DIB:  triclinic space group, P1̄ (no. 2), a = 7.4987(7) Å, b = 8.1906(12) Å, c = 11.6512(12) Å, α = 83.245(4)°, β = 84.695(3)°, γ = 86.135(3)°, V = 706.35(14) Å3, Z = 2, ρcalc = 2.43 g/cm3.