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: 7989006
• 负责人: RICHARD W SCOTT
• 金额: $ 49.99万
• 依托单位: POLYMEDIX, INC,
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989006
• 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; Screening procedure; 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; 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50亿临床病例和100万死亡病例。此外，耐药恶性疟原虫已成为一个主要问题。因此，发现新的抗疟疾药物类别以对抗耐药寄生虫是至关重要的。我们认为抗菌肽（AMPs）可能是一类新型抗疟药物的基础。amp是先天免疫系统的重要组成部分。amp对细菌、酵母菌、真菌表现出非常广谱的作用，通过特异性地破坏它们的膜而不是靶向蛋白质。许多AMPs的抗寄生虫活性也被报道，并被认为通过与它们对细菌的作用机制相似的机制杀死原生动物：与质膜相互作用，导致过度渗透，裂解和死亡。寄生虫对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，AMPs的作用部位是质膜，而不是任何特异性受体或细胞内蛋白靶点，这些靶点容易发生突变以逃避药物抑制。因此，对抗菌肽产生耐药性的可能性较小。然而，尽管AMPs具有良好的抗菌活性，但组织分布和毒性问题已经成为将这类昂贵肽转化为药物的障碍。PolyMedix已经开发出一系列小的非肽类AMPs (SMAMPs)，它们对细菌具有强大的广谱活性，并且对动物的毒性明显降低。我们提出smamp可能为一种本质上难以产生耐药性的新型抗疟药物提供基础。对PolyMedix的smamp进行了测试，发现几种smamp在亚微摩尔ic50和低细胞毒性的培养中杀死恶性疟原虫。重要的是，最受欢迎的药物对氯喹敏感和耐药的寄生虫都有活性。我们的假设是，它们通过扰乱食物液泡和其他可能的寄生膜而起作用，导致食物液泡的快速裂解和寄生虫的死亡。细菌中的抗菌剂膜靶点与产生耐药性的可能性较低有关，这将在恶性疟原虫中进行测试。这笔赠款的目标是验证和追求抗疟疾smamp用于治疗开发。I期部分通过体外和体内功效测试对这类化合物进行概念验证。II期阶段的目标是发现领先的候选治疗药物。使用smamp靶向寄生虫膜是治疗寄生虫病的一种高度创新和新颖的方法，使该项目与该领域的其他项目区别开来。