Structure-Based Design of Sortase Inhibitors for Anti-Infective Therapy

用于抗感染治疗的分选酶抑制剂的基于结构的设计

• 批准号: 7909173
• 负责人: Bing Li
• 金额: $ 30万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909173
• 关键词: Actinobacteria class; Actinomyces; Active Sites; Address; Adherence; Adhesions; Affinity; Animal Model; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacterial Adhesion; Bacterial Infections; Binding; Biochemical; Biological Assay; Cathepsin L; Cell Wall; Cell membrane; Cells; Cellular Assay; Chemicals; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Cysteine; Cysteine Proteinase Inhibitors; Defect; Development; Dose; Drug Design; Drug Kinetics; Enhancers; Enzymes; Exhibits; Family; Fibronectins; Genes; Genus staphylococcus; Goals; Gram-Positive Bacterial Infections; Health; Human; Immune; Immune response; Immunocompetent; In Vitro; Infection; Inhibitory Concentration 50; Lead; Listeria monocytogenes; Liver Microsomes; Membrane Proteins; Metabolism; Molecular Models; Nutrient; Oral; Patients; Peptides; Peptidoglycan; Peptidyltransferase; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Play; Positioning Attribute; Property; Protein Isoforms; Proteins; Recombinants; Research; Resistance; Role; Safety; Staphylococcus aureus; Streptococcus mutans; Streptococcus pneumoniae; Structure; Sulfhydryl Compounds; Surface; Techniques; TimeLine; Toxic effect; Virulence; Virulence Factors; absorption; antimicrobial; antimicrobial drug; base; chemotherapy; covalent bond; cytotoxic; cytotoxicity; design; divinyl sulfone; drug discovery; drug resistant bacteria; effective therapy; in vivo; inhibitor/antagonist; innovation; molecular modeling; mutant; novel; novel strategies; pathogen; phase 2 study; public health relevance; resistance mechanism; small molecule; sortase

DESCRIPTION (provided by applicant): The emergence of drug-resistant bacteria is an increasing health problem. Because of the resistance challenge, novel approaches which will not be subject to existing resistance mechanisms, are required for antimicrobial drug discovery. Targeting bacterial virulence for antimicrobial chemotherapy is an effective approach for bacterial infection. Sortase A is an attractive and validated antivirulent target, which catalyzes anchoring surface proteins on the bacterial cell membrane. Surface proteins contribute to bacterial adhesion, evasion of host immune response, nutrient acquisition and host cell invasion. Interference with the display of surface proteins on the bacterial cell membrane by inhibition of sortase A is an effective mechanistic approach to antibacterial therapy. Currently, no sortase inhibitors have been approved for treatment of bacterial infection. The overall goal of this project is to discover and develop small molecule inhibitors of sortase for anti-infective therapy. Our strategy is to use structure-based drug design (SBDD) to identify potent drug-like small molecules in a recombinant SrtA assay and a fibronectin-binding assay and position them for development into drugs for the treatment of Gram-positive bacterial infections. This strategy represents an innovative approach to the treatment of Gram-positive bacterial infections that will increase the efficacy of existing antibiotics at low doses, and decrease the development of antibiotic resistance. In preliminary studies, we have used the co-crystal structural information generated for Staphylococcus aureus SrtA and designed two classes of sortase A inhibitors based on a vinyl sulfone warhead template. Molecular modeling studies suggest that these two classes of vinyl sulfones will inactivate sortase by forming a reversible, covalent bond with the active site cysteine thiol functionality. The major milestone of this proposal will be the identification of selective lead compounds with potent sortase A inhibition (IC50 < 1 ?M) and low cytotoxicity (CC50 > 100 1 ?M). Lead compounds will display selectivity against a battery of profiling enzymes and will be pharmacokinetically acceptable in in vitro studies. Phase II will continue the development of these lead compounds and lead to the identification of a Clinical Development Candidate (CDC). PUBLIC HEALTH RELEVANCE: The overall goal of this project is to identify potent drug-like small molecules in a recombinant sortase A assay and a fibronectin-binding assay and position them for development them into drugs for the treatment of Gram-positive bacterial infections. Our strategy is to use structure- based drug design (SBDD) to define these inhibitors of sortase A. We will define sortase A inhibitors that are potent, selective in a battery of profiling enzymes, non-cytotoxic and exhibit favorable in vitro pharmacokinetic properties.

描述（由申请人提供）：耐药细菌的出现是一个日益严重的健康问题。由于耐药性挑战，抗菌药物的发现需要不受现有耐药机制影响的新方法。针对细菌毒力进行抗菌化疗是治疗细菌感染的有效方法。分选酶 A 是一种有吸引力且经过验证的抗毒靶标，可催化细菌细胞膜上的表面蛋白锚定。表面蛋白有助于细菌粘附、逃避宿主免疫反应、营养获取和宿主细胞入侵。通过抑制分选酶 A 来干扰细菌细胞膜上表面蛋白的展示是抗菌治疗的有效机制方法。目前，还没有分选酶抑制剂被批准用于治疗细菌感染。该项目的总体目标是发现和开发用于抗感染治疗的分选酶小分子抑制剂。我们的策略是使用基于结构的药物设计 (SBDD) 在重组 SrtA 测定和纤连蛋白结合测定中识别有效的药物样小分子，并将它们开发成治疗革兰氏阳性细菌感染的药物。该策略代表了一种治疗革兰氏阳性细菌感染的创新方法，它将提高低剂量现有抗生素的功效，并减少抗生素耐药性的发展。在初步研究中，我们利用金黄色葡萄球菌SrtA生成的共晶结构信息，设计了两类基于乙烯基砜弹头模板的分选酶A抑制剂。分子模型研究表明，这两类乙烯基砜将通过与活性位点半胱氨酸硫醇官能团形成可逆共价键来使分选酶失活。该提案的主要里程碑将是鉴定具有有效分选酶 A 抑制 (IC50 < 1 µM) 和低细胞毒性 (CC50 > 100 1 µM) 的选择性先导化合物。先导化合物将对一组分析酶表现出选择性，并且在体外研究中是药代动力学可接受的。 II 期将继续开发这些先导化合物，并确定临床开发候选药物 (CDC)。 公共健康相关性：该项目的总体目标是在重组分选酶 A 测定和纤连蛋白结合测定中鉴定有效的药物样小分子，并将其开发成治疗革兰氏阳性细菌感染的药物。我们的策略是使用基于结构的药物设计 (SBDD) 来定义这些分选酶 A 抑制剂。我们将定义分选酶 A 抑制剂，它们是有效的、对一系列分析酶具有选择性、无细胞毒性并表现出良好的体外药代动力学特性。