Carbohydrate-based Antiinfective Agents

碳水化合物类抗感染剂

• 批准号: 8325446
• 负责人: CHI-HUEY WONG
• 金额: $ 47.38万
• 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/8325446
• 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; Screening procedure; 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; 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药物可以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，代表了尚未开发的治疗方法。基于碳水化合物的抗感染药物的前景是它们不太容易演变为微生物抗性，因为碳水化合物配体本身是不变的，并且碳水化合物识别对于致病功能是必不可少的。因此，基于碳水化合物的抗感染药物可以更好地阻止耐药微生物菌株进化所带来的迫在眉睫的公共卫生威胁。拟议研究的目标是专门开发新的基于碳水化合物的抗感染药物，以解决最近病原菌和流感的耐药菌株的增加，如两个目标所述：1）细菌转糖基酶，以及2）流感外壳蛋白血凝素和神经氨酸酶。转糖基酶（TGase）是负责组装细菌细胞壁的碳水化合物骨架的酶：由于其识别肽聚糖的不变寡糖骨架，它是必需的、可获得的并且不易于演变抗生素抗性。我们的努力为TGase针对危险的革兰氏阳性耐甲氧西林金黄色葡萄球菌（MRSA）和万古霉素耐药肠球菌（VRE）菌株的期待已久的抗生素开发做好了准备。在扩展中，分枝杆菌TGase将被建立用于开发抗结核药物，由于多重和广泛耐药结核分枝杆菌（MDR-/XDR-TB）的惊人增长，这是非常需要的。提出了用于靶向革兰氏阳性和分枝杆菌TGases的基于碳水化合物的底物类似物、过渡态抑制剂和新型药物样基序的专门合成途径。血凝素（HA）和神经氨酸酶（NA）是流感病毒外壳糖蛋白，易受唾液酸衍生物的抑制，其干扰唾液酸苷（即以唾液酸结束的复合碳水化合物）的必要识别。它们也是适应性免疫应答的靶标，其可以产生针对抗原蛋白表位的中和抗体，特别是HA。需要改进抑制和免疫的策略，因为病毒突变的高比率导致对抗流感药物的抗性（例如，在2009年6级大流行爆发期间达菲抗性“猪流感”的迅速出现）和抗原漂移（即，保护性免疫）。流行病威胁的迫近进一步加快了这一需求。本文设计的抗流感剂集中于建立更高的耐药性屏障和理解耐药性突变如何影响NA-唾液酸糖苷相互作用。碳水化合物修饰的HA蛋白疫苗的策略，注意力集中在最大限度地提高交叉反应性免疫。