The objective of the proposed work is to develop and characterize potent aptamer-based biomaterials that recognize host cellular receptors based on a biomimetic strategy - polyvalency. Nature makes use of polyvalent interactions, involving the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another, to strengthen the avidity of interactions significantly. The proposed studies will use polyvalency to develop and characterize potent heterodivalent and polyvalent microbicides that bind to CCR5 receptors and prevent infection by a model pathogen, HIV. Although the use of cocktails of antiretroviral drugs has had a major impact on the treatment of AIDS in the developed world, there are problems associated with these regimens including serious side effects, high costs, and the emergence of resistant strains. In the context of the global pandemic, there remains a critical need for strategies to prevent the transmission of the virus. Given the lack of an effective HIV vaccine, an effective microbicidal formulation applied prior to intercourse to block the virus before infection is established remains our best hope to arrest this terrible pandemic in the short term. Moreover, the active components of such formulations must be potent, cost effective, and address the problem of emergence of viral resistance.
The first aim of the proposed work is to identify short oligonucleotide aptamers that bind to different domains of CCR5.
The second aim i s to optimize the biocompatibility and activity of aptamer-based heterodivalent and polyvalent inhibitors.
The third aim i s to characterize inhibitory efficac in vivo using a new humanized bone marrow/liver/thymus (huBLT) mouse model and to design formulations for the controlled release of the heterodivalent and polyvalent inhibitors over an extended period to improve microbicide acceptability. We anticipate that these novel heterodivalent and polyvalent inhibitors will effectively block CCR5-mediated entry of HIV into target cells. Active heterodivalent and polyvalent CCR5-targeted inhibitors should help address the important problem of resistance to HIV inhibitors because: CCR5 is a static target, not prone to the high mutation rate of HIV-1; persons with a genetic defect in CCR5 expression are highly resistant to infection with HIV-1, but are otherwise normal, healthy individuals; and most cases of HIV-1 transmission involve viral strains that use CCR5 for entry, and such strains predominate during the establishment of infection. The use of short aptamers will make the approach practical from a cost perspective. The proposed heterodivalent and polyvalent microbicides represent innovative new formulations that combine multiple interventions (ligands targeted towards different extracellular domains of CCR5) within a single molecule. We anticipate that our proposed research program will result in novel HIV microbicides with improved efficacy, safety, and acceptability, providing a powerful means to prevent the transmission of this globally-important pathogen.
The proposed work will focus on the engineering of nanoscale aptamer-based biomaterials for the potent and specific recognition of cellular receptors. These studies will contribute to a fundamental understanding of polyvalent biorecognition, which is important for the design of inhibitors and targeted delivery systems. The research is also relevant to public health because the design of heterodivalent and polyvalent receptor-directed molecules represents a powerful approach for preventing the transmission of pathogens and limiting the emergence of resistant strains.
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|Varner, Chad T; Rosen, Tania; Martin, Jacob T et al. (2015) Recent advances in engineering polyvalent biological interactions. Biomacromolecules 16:43-55|
|Patke, Sanket; Boggara, Mohan; Maheshwari, Ronak et al. (2014) Design of monodisperse and well-defined polypeptide-based polyvalent inhibitors of anthrax toxin. Angew Chem Int Ed Engl 53:8037-40|