Development of Small Antimicrobial Peptide Mimics as Drug-Resistant and Susceptib

开发具有耐药性和敏感性的小抗菌肽模拟物

• 批准号: 8516980
• 负责人: RICHARD W SCOTT
• 金额: $ 100万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516980
• 关键词: Acute; Adverse effects; Adverse reactions; Animals; Antibiotics; Antimalarials; Antimicrobial Resistance; Antiparasitic Agents; Bacteria; Benchmarking; Bioavailable; Biological Assay; Biological Availability; Cell membrane; Cells; Cessation of life; Chemicals; Chemistry; Chloroquine; Cholesterol; Clinical; Clinical Trials; Cryptosporidium; Cytolysis; Data; Development; Disease; Dose; Drug Design; Drug Formulations; Drug Interactions; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Enzymes; Exhibits; Food; Goals; Grant; Hepatocyte; Host Defense; Human; Immune system; Immunocompromised Host; In Vitro; Incidence; Individual; Infection; Inhibitory Concentration 50; Laboratories; Lead; Libraries; Liver; Malaria; Measures; Membrane; Modeling; Molecular; Multi-Drug Resistance; Mus; Mutate; No-Observed-Adverse-Effect Level; Oral; Outcome; Parasite resistance; Parasitemia; Parasites; Parasitic Diseases; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phospholipids; Plasma; Plasmodium falciparum; Process; Property; Protein Binding; Proteins; Protozoa; Quantitative Structure-Activity Relationship; Rattus; Regimen; Relapse; Reporting; Resistance; Resistance development; Rodent; Safety; Scheme; Series; Site; Specificity; Staphylococcal Infections; Structure-Activity Relationship; Synthesis Chemistry; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Toxoplasma; Translating; Vacuole; Work; Yeasts; analog; animal efficacy; antimicrobial; antimicrobial peptide; base; biodefense; combat; cost; cytotoxicity; design; dosage; efficacy testing; fungus; improved; in vivo; innovation; insight; killings; lead series; member; mouse model; novel; novel strategies; pathogenic bacteria; receptor; research study; resistant strain; safety study; scale up; screening; therapeutic development; treatment duration

DESCRIPTION (provided by applicant): Malaria is a global disease causing > 500 million clinical cases and > 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is crucial to discover new classes of drugs for anti-malarial drug design to combat resistant parasites. We propose that antimicrobial peptides (AMPs) may provide the basis of a novel class of antimalarials. AMPs are an essential component of the innate immune system. AMPs display very broad- spectrum action against bacteria, yeast, fungus by specifically disrupting their membranes rather than targeting proteins. Antiparasitic activities are also reported for a number of AMPs and are thought to kill protozoa by a mechanism similar to their mechanism of action against bacteria: interacting with plasma membranes, causing excessive permeability, lysis and death. Specificity for the parasite versus host cell is attributed to differences in phospholipid content and the lack of cholesterol in the protozoan membranes. Importantly, the site of action for AMPs is the plasma membrane and not any specific receptors or intracellular protein targets that can easily mutate to escape drug inhibition. Thus, the development of resistance to AMPs is less likely to occur. However, while AMPs have good antimicrobial activity, problems with tissue distribution and toxicity have presented obstacles to translating this expensive class of peptides into drugs. PolyMedix has developed series of small non-peptidic mimics of these AMPs (SMAMPs), which have robust, broad- spectrum activity against bacteria and markedly lower toxicity in animals. We propose SMAMPs may provide the basis of a novel class of antimalarials against which resistance will be intrinsically difficult to develop. SMAMPs from PolyMedix were tested and several kill Pl. falciparum parasites in culture having submicromolar IC50s and low cytotoxicity. Importantly, the top hits are active against both chloroquine-sensitive and resistant parasite lines. Our hypothesis is that they act through the perturbation of the food vacuole and possibly other parasitic membranes resulting in the rapid lysis of the food vacuole and parasite death. Membrane targets in bacteria for antimicrobials have been associated with a lower likelihood for developing resistance and this will be tested in Pl. falciparum. The goal of this grant is to validate and pursue antimalarial SMAMPs for therapeutic development. The Phase I portion generates proof-of-concept for this class of compounds through in vitro and in vivo efficacy testing. The Phase II segment aims to result in a discovery lead therapeutic candidate(s). Targeting parasite membranes using SMAMPs represents a highly innovative and novel approach to treating parasitic diseases and distinguishes this project from others in the field. Malaria is a global disease causing at least 500 million clinical cases and more than 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is paramount to discover new classes of drugs for anti- malarial drug design to combat resistant parasites. We propose to develop novel antimalarial therapeutics using small non-peptidic mimics of naturally-occurring antimicrobial peptides. These therapeutics should prove to be potent, active against resistant parasites and display a low incidence of resistance.

描述（由申请人提供）：疟疾是一种全球性疾病，每年造成> 5亿临床病例和> 100万死亡。此外，抗药性恶性疟原虫已成为一个主要问题。因此，至关重要的是要发现新的抗疟疾药物设计的药物类别，以打击耐药寄生虫。我们认为抗菌肽（AMP）可能为一类新的抗疟药物提供基础。AMP是先天免疫系统的重要组成部分。AMP通过特异性破坏细菌、酵母、真菌的膜而不是靶向蛋白质而显示出非常广谱的抗细菌、酵母、真菌作用。还报道了许多AMP的抗寄生虫活性，并且认为其通过与其对细菌的作用机制类似的机制杀死原生动物：与质膜相互作用，引起过度渗透性、溶解和死亡。寄生虫与宿主细胞的特异性归因于原生动物膜中磷脂含量的差异和胆固醇的缺乏。重要的是，AMP的作用位点是质膜，而不是任何特异性受体或细胞内蛋白靶点，这些受体或蛋白靶点可以容易地突变以逃避药物抑制。因此，不太可能发生对AMP的耐药性的发展。然而，尽管AMP具有良好的抗微生物活性，但组织分布和毒性问题已经阻碍了将这类昂贵的肽转化为药物。PolyMeidine已经开发了一系列这些AMP的小的非肽模拟物（SMAMP），其对细菌具有稳健的广谱活性并且在动物中具有显著较低的毒性。我们建议SMAMPs可能提供了一种新的抗疟药的基础，对这种抗疟药的耐药性本质上是难以发展的。测试了来自PolyMeidium的SMAMP，并且几种杀死了Pl.在培养物中的恶性疟原虫具有亚微摩尔IC 50和低细胞毒性。重要的是，最高命中对氯喹敏感和抗性寄生虫系都有活性。我们的假设是，它们通过扰动食物泡和可能的其他寄生虫膜，导致食物泡的快速溶解和寄生虫死亡。抗菌剂在细菌中的膜靶点与产生耐药性的可能性较低相关，这将在PI中进行测试。恶性疟原虫。这笔赠款的目标是验证和追求抗疟SMAMP的治疗发展。I期部分通过体外和体内功效测试生成这类化合物的概念验证。II期部分旨在发现领先的候选治疗药物。使用SMAMP靶向寄生虫膜代表了治疗寄生虫疾病的高度创新和新颖的方法，并将该项目与该领域的其他项目区分开来。 疟疾是一种全球性疾病，每年造成至少5亿临床病例和100多万人死亡。此外，抗药性恶性疟原虫已成为一个主要问题。因此，最重要的是发现新的药物类别的抗疟疾药物设计，以打击耐药寄生虫。我们建议开发新的抗疟治疗使用小的非肽模拟物的天然存在的抗菌肽。这些治疗剂应被证明是有效的，对耐药寄生虫有活性，并显示出较低的耐药性发生率。