Carbohydrate-based Antiinfective Agents

碳水化合物类抗感染剂

• 批准号: 8520158
• 负责人: CHI-HUEY WONG
• 金额: $ 44.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520158
• 关键词: Address; Affect; Anabolism; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Attention; Binding; Biochemical; Biological Assay; Capsid Proteins; Carbohydrates; Cell Wall; Cell surface; Communicable Diseases; Complex; Development; Diagnostic; Disease Outbreaks; Drug resistance; Drug resistance in tuberculosis; Enzymes; Epitopes; Event; Evolution; Exhibits; Extreme drug resistant tuberculosis; Glycoproteins; Goals; Grant; Hemagglutinin; Human; Immune response; Immune system; Immunity; Immunization; Infection; Influenza; Influenza vaccination; Inorganic Sulfates; Lead; Libraries; Life Cycle Stages; Ligands; Link; Masks; Methods; Monitor; Mutation; Mycobacterium tuberculosis; Nature; Neuraminidase; Oligosaccharides; Oseltamivir; Peptidoglycan; Pharmaceutical Preparations; Process; Proteins; Public Health; Research; Resistance; Resistance development; Resources; Route; Sialic Acids; Site; Structure; Structure-Activity Relationship; Therapeutic; Unspecified or Sulfate Ion Sulfates; Vaccines; Vancomycin resistant enterococcus; Vertebral column; Viral; analog; base; carbohydrate receptor; carbohydrate structure; combat; design; directed attention; glycosylation; high throughput screening; improved; influenza virus vaccine; inhibitor/antagonist; methicillin resistant Staphylococcus aureus; microbial; mycobacterial; neutralizing antibody; novel; novel therapeutics; pandemic disease; pathogen; pathogenic bacteria; pharmacophore; phosphonate; preference; prophylactic; receptor; resistant strain; scaffold; screening; swine flu; tool

DESCRIPTION (provided by applicant): Carbohydrate-based anti-infective agents can disrupt complex carbohydrate recognition events vital to the infective mechanisms of pathogens, representing an untapped wealth of therapeutics. The promise of carbohydrate-based anti-infective is that they are less prone to the evolution of microbial resistance, because, carbohydrate ligands themselves are invariant, and carbohydrate recognition is essential to pathogenic function. As such, carbohydrate-based anti-infective can better thwart the looming public health threats posed by the evolution of resistant microbial strains. The goals of the proposed research are to specifically develop new carbohydrate-based anti-infective agents that address the recent rise of resistant strains of pathogenic bacteria and influenza, as detailed in two aims targeting: 1) bacterial transglycosylase, and 2) the influenza coat proteins hemagglutinin and neuraminidase. Transglycosylase (TGase) is the enzyme responsible for assembling the carbohydrate backbone of the bacterial cell wall: it is essential, accessible, and less prone to evolving antibiotic resistance due to its recognition of the invariant oligosaccharide backbone of the peptidoglycan. Our efforts have primed TGase for long-awaited antibiotic development against dangerous gram-positive strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In extension, the Mycobacterial TGase will be established for the development of anti-tuberculosis agents, which are in great need due to the alarming rise of multi- and extensively-drug resistant Mycobacterium tuberculosis (MDR-/XDR-TB). Routes for the specialized synthesis of carbohydrate-based substrate analogs, transition state inhibitors, and novel drug- like motifs are proposed for targeting gram-positive and Mycobacterial TGases. Hemagglutinin (HA) and neuraminidase (NA) are influenza coat glycoproteins that are susceptible to inhibition by sialic acid derivatives, which interfere with necessary recognition of sialosides (i.e. complex carbohydrates that end with a sialic acid). They are also targets of the adaptive immune response, which can generate neutralizing antibodies to antigenic protein epitopes, particularly with HA. Strategies for inhibition and immunization need to be improved, as high rates of viral mutation lead to resistance against antiinfluenza agents (e.g., the rapid emergence of Tamiflu resistant "swine flu" during the 2009 level-6 pandemic outbreak) and antigenic drift (i.e., escape from protective immunity). Looming pandemic threats further hasten this need. Antiinfluenza agents are designed herein with focus on establishing a higher barrier to resistance and understanding how resistant mutations affect NA-sialoside interactions. A strategy for a carbohydrate-modified HA protein vaccine is presented, with attention directed toward maximizing cross-reactive immunity.

描述（由申请人提供）：基于碳水化合物的抗感染剂会破坏对病原体感染机制至关重要的复杂碳水化合物识别事件，代表未开发的大量治疗剂。基于碳水化合物的抗感染性的承诺是，它们不太容易发生微生物耐药性，因为碳水化合物配体本身是不变的，碳水化合物识别对于致病功能至关重要。因此，基于碳水化合物的抗感染可以更好地挫败抗性微生物菌株进化所带来的迫在眉睫的公共卫生威胁。拟议的研究的目标是专门开发新的基于碳水化合物的抗感染剂，这些抗感染剂涉及致病细菌和流感抗性菌株最近的升高，如两个针对性的目标：1）细菌透糖基酶，以及2）2）流感蛋白蛋白质蛋白质蛋白质蛋白质蛋白质蛋白血液素和神经酶。糖基化酶（TGASE）是负责组装细菌细胞壁的碳水化合物主链的酶：由于其认识到肽聚糖的不变性寡糖基链，它是必不可少的，易于访问且不太容易发生抗生素耐药性的酶。我们的努力已经为期待已久的抗生素发展提供了TGase，以抵抗耐甲氧西林抗甲氧西林的金黄色葡萄球菌（MRSA）和耐万古霉素的肠球菌（VRE）的危险革兰氏阳性株。总体而言，将建立分枝杆菌TGase用于开发抗结核剂，由于多种和广泛的抗药性结核病（MDR-/XDR-TB）令人震惊，这非常需要。提出了用于靶向革兰氏阳性和分枝杆菌TGase的专门合成基于碳水化合物的底物类似物，过渡态抑制剂和新型药物基序的途径。血凝素（HA）和神经氨酸酶（Na）是流感外套糖蛋白，易于受到唾液酸衍生物抑制的影响，唾液酸衍生物会抑制，这会干扰对唾液酸的必要识别（即，复杂的碳水化合物与唾液酸结束）。它们也是适应性免疫反应的靶标，可以产生对抗原蛋白表位的中和抗体，尤其是HA。需要改善抑制和免疫的策略，因为高病毒突变速率会导致对抗氟烷剂的抵抗力（例如，在2009年6级大流行暴发期间，tamiflu抗性“猪流感”的迅速出现）和抗原漂移（即从保护性免疫中逃脱）。迫在眉睫的大流行威胁进一步加快了这一需求。抗氟烯氮剂的设计在本文中设计，重点是建立较高的耐药性和了解耐药性突变如何影响Na-Sialoside相互作用的障碍。提出了一种碳水化合物改性HA蛋白疫苗的策略，其注意力旨在最大化交叉反应性免疫。