Engineering Nanoscale Aptamer-based Biomaterials that Target Cellular Receptors

针对细胞受体的工程纳米适体生物材料

基本信息

批准号：
8711082
负责人：
Ravi S. Kane
金额：
$ 31.11万
依托单位：
RENSSELAER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-06 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711082
关键词：
AIDS Vaccines Acquired Immunodeficiency Syndrome Address Adverse effects Anti-Retroviral Agents Avidity Binding Biocompatible Materials Biological Biomimetics Bone Marrow CCR5 gene Cells Chemokine (C-C Motif) Receptor 5 Drug Formulations Engineering Evolution Extracellular Domain HIV HIV Infections HIV vaccine HIV-1 Individual Infection Infection prevention Intervention Ligands Liver Mediating Methods Modeling Mutation Nature Oligonucleotides Persons Pharmaceutical Preparations Public Health Regimen Research Resistance Safety System Thymus Gland Vaccines Viral Virus Work aptamer base biomaterial compatibility cellular targeting chemokine receptor controlled release cost cost effective design improved in vivo inhibitor/antagonist innovation interest microbicide model design mouse model nanoscale novel pandemic disease pathogen prevent programs receptor resistant strain scaffold single molecule targeted delivery transmission process viral resistance

项目摘要

DESCRIPTION (provided by applicant): 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 is to optimize the biocompatibility and activity of aptamer-based heterodivalent and polyvalent inhibitors. The third aim is 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.