Self Assembling High Affinity Peptides for Point of Care Drug-Device Combinations

用于护理点药物-器械组合的自组装高亲和力肽

• 批准号: 7536285
• 负责人: Shrikumar Ambujakshan Nair
• 金额: $ 30万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536285
• 关键词: Address; Affinity; Antibiotics; Atomic Force Microscopy; Bacteria; Binding; Biochemical; Biocompatible Materials; Biological Assay; Biomechanics; Biopolymers; Cardiovascular Surgical Procedures; Cells; Characteristics; Chemicals; Chemistry; Condition; Coupling; Data; Devices; Drug Delivery Systems; Drug Kinetics; Failure; Friction; Goals; Growth Factor; Implant; In Vitro; Infection; Investigation; Life; Limb structure; Link; Mediating; Medical; Medical Device; Metals; Methods; Microbial Biofilms; Nanostructures; Nature; Numbers; Operative Surgical Procedures; Oral; Orthopedics; Peptide Synthesis; Peptides; Phage Display; Pharmaceutical Preparations; Phase; Plastics; Polymers; Process; Property; Proteins; Public Health; Range; Rate; Research; Resistance; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Societies; Solutions; Specific qualifier value; Specificity; Standards of Weights and Measures; Structure; Surface; System; Techniques; Technology; Testing; Tissues; To specify; Vancomycin; antimicrobial; antimicrobial drug; aqueous; base; chemical property; clinical application; combinatorial; concept; craniomaxillofacial; density; improved; interfacial; microbial colonization; new technology; novel; point of care; programs; protein aminoacid sequence; self assembly; surface coating

DESCRIPTION (provided by applicant): Infection surrounding metal implants is a common and sometimes devastating cause of implant failure in a number of fields including oral, craniomaxillofacial (CMF), orthopedic, and cardiovascular surgery. These infections, which arise from the establishment of biofilms on device surfaces, not only necessitate new surgeries but in themselves present a significant threat to life and limb. New technologies that decrease microbial colonization of metal implants would reduce these infections, mitigating their severe consequences. Affinergy is developing bifunctional affinity peptides, called interfacial biomaterials (IFBMs), that promote the attachment and retention of drugs, proteins, and cells on the surface of medical devices. Using phage display, we have identified specific peptide sequences that bind with high affinity to a number of metals and another specific set of peptide sequences that bind with high affinity to vancomycin. Synthesizing these sequences as a single IFBM using appropriate linkers permits the attachment of vancomycin directly to the surface of a metal implant at point-of-care. Thus far however, Affinergy's drug delivery coatings have been limited to arranging a 1-to-1 interaction between a peptide molecule and an antibiotic. While we have observed promising preliminary data with this technique using antibiotics, there are likely additional drugs we might target if the amount of drug loaded to a given surface could be increased. Because our coatings are comprised of high affinity peptides, expanding our technology using an approach which employs the structural and chemical properties of peptides would be desirable. We therefore propose here the coupling of our material and drug-binding peptides to sequences which assemble into higher-order nanostructures. Our goal is to generate a three-dimensional surface coating from self-assembling affinity peptides, capable of binding and retaining significantly higher concentrations of a drug to a device surface. Data from our preliminary studies, suggest that peptides capable of limited self-assembly bind to materials with improved resistance to chemical challengers compared to traditional IFBMs. This research program attempts to continue these studies, toward developing a self assembling coating system, attaching vancomycin to metal. In Aim 1, we will synthesize and characterize vancomycin and metal binding peptides with the addition of various self-assembling peptide sequences. In Aim 2, we will characterize the biochemical and biophysical nature of self-assembling affinity peptides in solution and on metal surfaces. We will compare the loading density, on-rate, and release of vancomycin from metal coated with traditional IFBMs and new self-assembling affinity peptides. Finally, in Aim 3, we will characterize the anti-microbial activity of vancomycin linked to metals with traditional IFBMs and self-assembling affinity peptides. Successful completion of these aims would encourage us to expand self-assembling affinity peptides to other clinical applications utilizing additional combinations of Affinergy drug, protein, cell, and material affinity peptides. Public Health Relevance: Infection surrounding metal hardware is a common and sometimes devastating cause of implant failure in a number of medical fields including oral, craniomaxillofacial (CMF), orthopedic, and cardiovascular surgery. Arising from the establishment of pathogenic biofilms on device surfaces, these infections not only necessitate new surgeries but in themselves present a significant threat to life and limb. The biofilm bacteria that establish themselves on metal hardware are essentially impossible to eradicate by any means except explantation. Methods that decrease infection rates associated with metal implants would clearly benefit society. We propose to develop a self-assembling affinity peptide coating that will promote attachment of antibiotics at point of care to a wide range of metal implants to decrease microbial colonization on their surfaces.

描述（由申请人提供）：围绕金属植入物的感染是在许多领域的常见原因，有时是造成植入物失败的原因，包括口腔，颅骨骨膜（CMF），骨科和心血管外科手术。这些感染是由在设备表面上建立生物膜的，不仅需要新的手术，而且还需要对生命和肢体构成重大威胁。减少金属植入物微生物定植的新技术将减少这些感染，从而减轻它们的严重后果。 Affinergy正在开发双功能亲和肽，称为界面生物材料（IFBMS），这些肽促进了药物，蛋白质和细胞在医疗设备表面上的附着和保留。使用噬菌体显示，我们已经确定了与许多金属和另一组特定的肽序列结合的特定肽序列，并与高亲和力结合到万古霉素。使用适当的接头将这些序列合成为单个IFBM，允许将万古霉素直接连接到护理点的金属植入物表面。然而，到目前为止，Affinergy的药物输送涂层仅限于在肽分子和抗生素之间排列1比1的相互作用。尽管我们使用抗生素观察到有希望的初步数据，但如果可以增加到给定表面的药物量增加，我们可能会针对其他药物。因为我们的涂料由高亲和力肽组成，所以希望使用采用肽的结构和化学特性的方法扩展我们的技术。因此，我们在这里提出了将材料和药物结合肽偶联到组装成高阶纳米结构的序列。我们的目标是通过自组装亲和力肽产生三维表面涂层，能够结合并保持更高浓度的药物与设备表面。来自初步研究的数据表明，与传统的IFBM相比，自我组装有限的肽与化学挑战者的抵抗力提高了材料。 该研究计划试图继续这些研究，以开发一个自组装涂料系统，将万古霉素附在金属上。在AIM 1中，我们将通过添加各种自组装肽序列来合成并表征万古霉素和金属结合肽。在AIM 2中，我们将表征溶液和金属表面上自组装亲和肽的生化和生物物理性质。 我们将比较涂有传统的IFBM和新的自组装亲和肽的金属中万古霉素的负载密度，速率和释放。最后，在AIM 3中，我们将表征与传统IFBM和自组装亲和肽的金属相关的万古霉素的抗微生物活性。这些目标的成功完成将鼓励我们利用Affinergy药物，蛋白质，细胞和材料亲和力肽的其他组合，将自组装亲和肽扩展到其他临床应用。 公共卫生相关性：围绕金属硬件的感染是在许多医疗领域的植入物衰竭的常见原因，包括口腔，颅颌面（CMF），骨科和心血管手术。 这些感染是由在装置表面上建立致病性生物膜的，不仅需要新的手术，而且还对生命和肢体构成了重大威胁。除了露天外，基本上不可能通过任何方式根除在金属硬件上建立自己的生物膜细菌。降低与金属植入物相关的感染率的方法显然会使社会受益。我们建议开发一种自组装亲和肽涂料，该涂层将促进抗生素在护理点上的附着，以减少其表面上的微生物定植。