Ampetoids as Biostable Functional Mimics of Antimicrobial Peptides

Ampetoids 作为抗菌肽的生物稳定功能模拟物

• 批准号: 7572890
• 负责人: Annelise Emily Barron
• 金额: $ 34.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7572890
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Address; Adsorption; Amides; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Antineoplastic Agents; Bacteria; Behavior; Binding; Biomimetics; Biophysics; Calorimetry; Cancer cell line; Carpet; Cell Culture Techniques; Cell membrane; Cells; Chemistry; Chimera organism; Clinical Trials; Communicable Diseases; Complement; Complex; Computer Simulation; Cytolysis; Development; Devices; Digestion; Discrimination; Engineering; Environment; Erythrocytes; Escherichia coli; Extravasation; Family; Film; Fluorescence Resonance Energy Transfer; Glycine; Goals; Hemolysis; Host Defense; Human; Human Cell Line; Infection; Investigation; Lead; Lipid Bilayers; Lipids; Mammalian Cell; Membrane; Metabolic; Modeling; Molecular; N-substituted Glycines; Oligonucleotides; Organism; Pattern; Peptide Hydrolases; Peptides; Peptoids; Pharmacologic Substance; Phase; Predisposition; Proteolysis; Protocols documentation; Relative (related person); Research Personnel; Research Project Grants; Resistance; Roentgen Rays; Serum; Side; Solid; Solutions; Source; Spectrum Analysis; Staging; Structure; Structure-Activity Relationship; Surface; System; Testing; Time; Titrations; Toxic effect; Variant; Vesicle; Work; analog; analytical ultracentrifugation; antimicrobial; antimicrobial peptide; aqueous; base; cytotoxicity; design; driving force; falls; fluorexon; functional mimics; immunogenic; in vivo; insight; interest; killings; magainin; microorganism; natural antimicrobial; novel; pathogen; peptide L; peptidomimetics; programs; resistant strain; tool

DESCRIPTION (provided by applicant): We propose to create and study a new family of biomimetic oligomers for antibacterial applications. In particular, we aim to create biostable, functional mimics of natural antimicrobial peptides (AMPs), which are an integral and effective part of the host-defense systems of myriad organisms ranging from humans to bacteria. By preferentially binding to and disrupting or permeating bacterial cell membranes, these surface- active peptides are able to kill a broad spectrum of microorganisms. Many are also selective, causing no harm to mammalian cells. The killing mechanism, while imperfectly understood, is sufficiently general that bacteria have been unable to evolve resistance to AMPs over millions of years. Thus, good functional mimics of AMPs hold forth the promise of serving as a new class of antibiotic compounds, which could act in solution directly or be tethered to the surfaces of biomedical devices to stave off infection. We propose to create non-natural mimics of AMPs, since peptides themselves are vulnerable to proteolysis and hence degrade too rapidly in the body, and moreover because peptides are often immunogenic in vivo. In particular, our novel mimics will be based on amphipathic, sequence-specific oligo-N-substituted glycines ("peptoids"). Peptoids are quite similar in structure to peptides, yet are protease-resistant. They are easily synthesized by a high-yielding, solid-phase protocol that allows the easy incorporation of biomimetic side chains. Moreover, peptoids can be designed to form stable, biomimetic helices that keep their folded structure in both aqueous and biomembrane environments, and which are highly resistant to denaturation. In preliminary work, we have shown that certain peptoid sequences (9-17mers) designed to mimic the amphipathic sequence patterning and helical structure of antimicrobial peptides are potent and selective antibacterials (MIC ~ 4 ¿M against E. coli and 820 nM against B. subtilis, with negligible hemolysis at the E. coli MIC). We propose to further study and develop these compounds, by (1) exploring structure-function relationships and mechanism(s) of action through detailed biophysical studies of a "basis set" of closely related peptoids with differing potency/selectivity profiles, (2) creating novel peptoids that mimic structural motifs of natural AMPs, including peptoids that are lipidated, cyclized, and kinked; (3) testing their antibiotic activity against antibiotic-resistant bacteria as well as early-stage investigation of their toxicity to human cells.

描述（由申请人提供）：我们提议创建和研究一个新的抗菌应用的仿生低聚物家族。特别是，我们的目标是创造生物稳定的，功能性的天然抗菌肽（AMPs）仿制品，这是从人类到细菌的无数生物宿主防御系统中不可或缺的有效部分。通过优先结合和破坏或渗透细菌细胞膜，这些表面活性肽能够杀死广泛的微生物。许多也是选择性的，不会对哺乳动物细胞造成伤害。这种杀伤机制虽然还不完全清楚，但已经足够普遍，以至于细菌在数百万年的时间里都无法进化出对抗菌肽的耐药性。因此，amp的良好功能模拟物有望成为一种新型抗生素化合物，它可以直接在溶液中起作用，也可以附着在生物医学设备的表面，以避免感染。我们建议创建amp的非天然模拟物，因为肽本身容易受到蛋白质水解，因此在体内降解得太快，而且因为肽在体内通常具有免疫原性。特别是，我们的新型模拟物将基于两亲性，序列特异性低聚n -取代甘氨酸（“类肽”）。类肽在结构上与多肽非常相似，但具有蛋白酶抗性。它们很容易通过高产的固相方案合成，可以很容易地结合仿生侧链。此外，类肽可以被设计成形成稳定的仿生螺旋，在水环境和生物膜环境中保持其折叠结构，并且具有高度的抗变性能力。在初步工作中，我们已经证明，某些肽类序列（9-17mers）被设计成模拟抗菌肽的两亲性序列模式和螺旋结构，是有效的和选择性的抗菌肽（对大肠杆菌的MIC ~ 4¿M和对枯草芽孢杆菌的820 nM，在大肠杆菌的MIC上可以忽略溶血作用）。我们建议进一步研究和开发这些化合物，通过(1)通过对具有不同效价/选择性的密切相关肽的“基础集”进行详细的生物物理研究来探索结构-功能关系和作用机制，(2)创建模仿天然AMPs结构基序的新型肽，包括脂化，环化和扭结的肽类；(3)检测其对耐药菌的抗菌活性以及对人体细胞毒性的早期研究。