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(申请人提供)：基于碳水化合物的抗感染剂可以破坏复杂的碳水化合物识别事件，这对病原体的感染机制至关重要，代表着尚未开发的治疗财富。基于碳水化合物的抗感染药物的前景是它们不太容易发生微生物耐药性的进化，因为，碳水化合物配体本身是不变的，而碳水化合物识别对致病功能是必不可少的。因此，以碳水化合物为基础的抗感染药物可以更好地挫败耐药微生物菌株进化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基于碳水化合物的新的抗感染剂，以应对最近出现的病原菌和流感耐药菌株的上升，具体有两个目标：1)细菌转糖基酶，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：它是必不可少的，可获得的，由于它识别肽聚糖的不变寡糖骨架，不太容易产生抗生素耐药性。我们的努力已经为TGase开发期待已久的抗生素开发做好了准备，以对抗危险的耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌(VRE)。此外，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)的惊人上升，迫切需要这些药物。提出了针对革兰氏阳性和分枝杆菌TGase的碳水化合物底物类似物、过渡态抑制剂和新型类药物基序的专门合成路线。血凝素(HA)和神经氨酸酶(NA)是流感衣壳糖蛋白，容易受到唾液酸衍生物的抑制，干扰对唾液酸苷(即以唾液酸结尾的复杂碳水化合物)的必要识别。它们也是适应性免疫反应的靶标，可以产生针对抗原蛋白表位的中和抗体，特别是与HA的中和抗体。需要改进抑制和免疫战略，因为高病毒变异率导致对抗流感药物的抗药性(例如，在2009年6级大流行期间迅速出现抗达菲的“猪流感”)和抗原漂移(即逃避保护性免疫)。迫在眉睫的大流行威胁进一步加速了这一需求。抗流感药物在这里的设计重点是建立更高的耐药性屏障，并了解耐药性突变如何影响NA-唾液酸苷的相互作用。提出了一种碳水化合物修饰的HA蛋白疫苗的策略，关注的是最大化交叉反应免疫。