Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide entry inhibitors.

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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 microg mL(-1)) for the 25 mol % functionalized polymers to 11 nM (1 microg mL(-1)) for the 75 mol % benzoboroxole-functionalized polymers. These polymers exhibited minimal cytotoxicity after 24 h exposure to a human vaginal cell line.





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Jay, Julie I, Bonnie E Lai, David G Myszka, Alamelu Mahalingam, Kris Langheinrich, David F Katz and Patrick F Kiser (2010). Multivalent benzoboroxole functionalized polymers as gp120 glycan targeted microbicide entry inhibitors. Mol Pharm, 7(1). pp. 116–129. 10.1021/mp900159n Retrieved from

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David F. Katz

Nello L. Teer, Jr. Distinguished Professor of Biomedical Engineering, in the Edmund T. Pratt, Jr. School of Engineering

Dr. Katz's research interests emphasize methods for prophylaxis against STD's, including topical microbicides, and for contraception.  Core perspectives and approaches include mass transport phenomena and biofluid mechanics; rheology and imaging, both in vitro and in vivo.  These are integrated to fundamental biological, pathological, and clinical processes and needs for improvement.

Context. According to the Joint United Nations Programme on HIV/AIDS, 40 million people worldwide are currently living with AIDS. Even 13 years ago, in 2003, 3 million people died of AIDS and 5 million new people became infected. These epidemiological figures are not significantly improving. Prevention of initial infection by HIV, as well as treatment of the AIDS disease, is critical to combating this terrible worldwide pandemic. Vaccines are one type of AIDS prevention modality, and there is much current research on them. However, this research is expected to require about another 6 - 10 years before efficacious products might become available, and there is no guarantee that successful vaccines will be developed, even in this extended time frame. An alternative prevention method is the use of topical formulations (e.g. gels, foams, intravaginal rings, suppositories, etc.) that a woman inserts into her reproductive tract and which prevent HIV (or other pathogens) from initiating infection. Some of these can also be applied rectally to prevent infection in that compartment. Academic and industrial researchers are currently developing and evaluating a new class of compounds, termed topical microbicides. These compounds kill or dysfunctionalize HIV or other target pathogens upon contact in the female reproductive tract. To-date, microbicide research has been directed almost exclusively toward discovery of new, improved microbicidal compounds. There has been virtually no companion effort on rational design of the formulations which women apply and which deliver microbicides to the target pathogens. We do not yet understand what physical and chemical properties microbicidal formulations should have in order to be most effective in preventing infection. Objective standards for evaluation of such formulations do not exist. The effectiveness of microbicidal formulations depends upon their ability to coat the surfaces of the lower reproductive tract, and to remain in place during the time when a woman is exposed to HIV. Our research group is pioneering analysis of the physical and chemical mechanisms responsible for such distribution and retention of microbicidal formulations (termed deployment) and for the delivery of the microbicidal molecules to target tissues, fluids and the pathogens themselves. This work is being translated to practical application in the evaluation of current candidate microbicidal formulations and in development of improved ones.

Our work also focuses upon methods of contraception, drawing upon Dr. Katz's vast experience in working in this field and in reproductive biology and medicine more broadly.  in particular, we are working on methods, primarily for use by women and under their control, that simultaneously provide contraceptive protection, and protection and HIV and other sexually transmitted pathogens, e.g. human papilloma virus (HPV) and herpes simplex virus (HSV).

Our research on microbicidal formulation deployment and drug delivery utilizes the methods of mechanical, chemical, electrical and optical engineering and materials science. Our work integrates two types of research: (1) we are undertaking fundamental studies of the mechanisms of formulation deployment and delivery; and (2) we are imaging and analyzing the distributions of formulations over the tissue surfaces of the lower reproductive tract in women, and the concentrations and transport of drugs from formulations onto and into luminal fluids and mucosal tissues. The fundamental studies have two components: theoretical analyses of fluid mechanical and other mass transport processes underlying deployment and drug delivery are linked to experimental simulations (in the laboratory) of salient flow and mass transport mechanisms. For example we developed a spectrophotometric method for analyzing microbicide diffusion from a formulation into cervical mucus. We have built experimental simulations of how gravity and the squeezing forces of vaginal epithelial surfaces cause a formulation to flow over those surfaces. We have built a simulation of how mixing of a microbicidal formulation with ambient in vivo fluids (e.g. vaginal fluid, semen) alters the formulation's properties and, therefore, its tendency to flow and adhere to epithelial surfaces. We also perform experimental measurements of fundamental material properties of formulations such as rheological and surface properties. These serve as inputs to the theoretical models of mass transport and flow. The mathematical models reveal particular relationships between properties of formulations and deployment and delivery characteristics.

We also measure in women the spreading and retention in the vagina of different vaginal formulations.  Our human studies are conducted in the clinic of the Department of Obstetrics and Gynecology at the Duke Medical Center. We apply a new, unique imaging instrument built by us, that shares some features with the endoscopes currently used clinically to visualize some interior regions of the body. Our instrument measures the local thickness of coating of the vaginal surfaces with a test formulation. It detects 'bare spots' of uncoated tissue that might be particularly vulnerable to infection. We have also pioneered use of optical methods to measure local drug concentrations, as they are transported from their vehicles into luminal fluids and mucosal tissues.  This latter work has initially been in vitro. We are currently working to expand it to direct in vivo measurements, which will be a breakthrough technology in analyzing mucosal drug delivery.

The above biophysics and biomedical engineering based work is also integrated to behavioral studies of users' perceptions and preferences of different contraceptive and STD prophylactic products.  The goal is to improve willingness to use these products, by designing them with properties and dosage regimens that achieve their pharmacological goals simultaneously with their user friendliness.

Collectively, our computational, in vitro and in vivo studies are integrated in creating new perspective and algorithms for product design and performance evaluation.  They are currently being applied in development of a number of products in the HIV/STD prevention and contraception pipelines.

Our research has been sponsored by the National Institutes of Health, the US Food and Drug Administration (FDA), the American Foundation for AIDS Research, the US Agency for International Development, the Population Council, and the CONRAD Program.

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